Pulmonary manifestations, treatments and outcomes of IgG4-related disease-a systematic literature review.

Immunoglobulin G4-related disease (IgG4-RD) is a multisystem fibroinflammatory condition. A consistent feature of many cases is pulmonary infiltrates, or respiratory failure. This systematic literature review aims to summarise the pulmonary manifestations of IgG4-RD, including clinical outcomes and treatment. This review was registered on PROSPERO (CRD42023416410). Medline, Embase and Cochrane databases were searched for articles discussing IgG4-RD syndrome. Information was extracted on demographics, type and prevalence of pulmonary manifestations, treatment and clinical outcomes. Initially, after deduplication, 3123 articles were retrieved with 18 ultimately included. A pooled total of 724 patients with IgG4-RD were included, 68.6% male, mean age 59.4 years (SD 5.8) at disease onset. The most frequently described pulmonary manifestation was mediastinal lymphadenopathy (n = 186, 48.8%), followed by pulmonary nodules (n = 151, 39.6%) and broncho-vascular thickening (n = 85, 22.3%). Where treatment was reported, the majority of patients received glucocorticoids (n = 211, 93.4%). Other immunosuppressive therapy included cyclophosphamide (n = 31), azathioprine (n = 18), with mycophenolate mofetil (n = 6), rituximab (n = 6), methotrexate (n = 5) and other unspecified immunomodulators (50). Clinical outcomes were reported in 263 patients, where 196 patients had remission of their disease, 20 had relapse, 35 had stable disease, four had progression and eight patients died from complications of IgG4-RD. This systematic review summarises pulmonary manifestations, treatments and outcomes in patients with IgG4-RD. Pulmonary involvement in IgG4-RD is relatively common, leading to high levels of morbidity and mortality. Glucocorticoids remain the mainstay of treatment, but further work is required to explore the management of patients with pulmonary manifestations in association with IgG4-RD.

Lymphadenopathy at the crossroad between immunodeficiency and autoinflammation: An intriguing challenge.

Lymphadenopathies can be part of the clinical spectrum of several primary immunodeficiencies, including diseases with immune dysregulation and autoinflammatory disorders, as the clinical expression of benign polyclonal lymphoproliferation, granulomatous disease or lymphoid malignancy. Lymphadenopathy poses a significant diagnostic dilemma when it represents the first sign of a disorder of the immune system, leading to a consequently delayed diagnosis. Additionally, the finding of lymphadenopathy in a patient with diagnosed immunodeficiency raises the question of the differential diagnosis between benign lymphoproliferation and malignancies. Lymphadenopathies are evidenced in 15-20% of the patients with common variable immunodeficiency, while in other antibody deficiencies the prevalence is lower. They are also evidenced in different combined immunodeficiency disorders, including Omenn syndrome, which presents in the first months of life. Interestingly, in the activated phosphoinositide 3-kinase delta syndrome, autoimmune lymphoproliferative syndrome, Epstein-Barr virus (EBV)-related lymphoproliferative disorders and regulatory T cell disorders, lymphadenopathy is one of the leading signs of the entire clinical picture. Among autoinflammatory diseases, the highest prevalence of lymphadenopathies is observed in patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) and hyper-immunoglobulin (Ig)D syndrome. The mechanisms underlying lymphoproliferation in the different disorders of the immune system are multiple and not completely elucidated. The advances in genetic techniques provide the opportunity of identifying new monogenic disorders, allowing genotype-phenotype correlations to be made and to provide adequate follow-up and treatment in the single diseases. In this work, we provide an overview of the most relevant immune disorders associated with lymphadenopathy, focusing on their diagnostic and prognostic implications.

Lymphadenopathy in IgG4-related disease: a phenotype of severe activity and poor prognosis, with eotaxin-3 as a new biomarker.

OBJECTIVE: To clarify relevant proteins and clinical characteristics of a phenotype of IgG4-related disease (IgG4-RD) with lymphadenopathy. METHODS: We enrolled patients newly diagnosed with IgG4-RD in our department between January 2000 and June 2018 and performed proteomic analysis to measure serum concentrations of 1305 proteins. We extracted proteins overexpressed in patients with IgG4-RD with lymphadenopathy by comparing between those with lymphadenopathy, those without lymphadenopathy and healthy controls. We further reviewed all the patients with IgG4-RD in our institution and investigated the characteristics and prognosis of the patients with IgG4-RD with lymphadenopathy. RESULTS: Eighty-five patients with IgG4-RD were enrolled, of which, 55% had lymphadenopathy. Proteomic analysis in 31 patients with IgG4-RD and 6 healthy controls revealed that eotaxin-3 was a potential serum biomarker in the patients with lymphadenopathy versus those without lymphadenopathy and healthy controls. A cohort of 85 patients with IgG4-RD demonstrated that patients with lymphadenopathy showed a significantly higher serum IgG4, IgG4:IgG ratio, IgG4-RD responder index and eosinophilia (P < 0.001 for all), irrelevant of the extent to which organ involvement developed. Patients with lymphadenopathy treated with glucocorticoid alone relapsed with significantly higher rates than those without lymphadenopathy (P = 0.03). CONCLUSION: Lymphadenopathy in IgG4-RD represents a phenotype associated with high disease activities, eosinophilia and relapsing disease. Eotaxin-3 is a novel biomarker related to IgG4-RD with lymphadenopathy.

Case report on mesangial proliferative glomerulonephritis with multicentric Castleman's disease: Approach to the onset mechanism of immunoglobulin A nephropathy.

Galactose-deficient immunoglobulin A1 (Gd-IgA1) was recently identified as a critical effector molecule in the pathogenesis of IgA nephropathy (IgAN). Gd-IgA1 is produced by the mucosal immune system. IgAN is thought to develop because of the deposition of a circulating immune-complex containing Gd-IgA1 in the kidney. Multicentric Castleman's disease (MCD) is a rare non-neoplastic lymphoproliferative disorder. As an etiology model, hypercytokinemia, including increased levels of interleukin-6, is the primary pathogenesis of many MCD cases. Here, we present two cases of mesangial proliferative glomerulonephritis with MCD. According to renal biopsy findings, one was diagnosed with non-IgAN and the other with IgAN. Surprisingly, in both cases, Gd-IgA1 was produced by plasma cells in the lymph nodes, suggesting that Gd-IgA1 production alone does not cause IgAN; rather, it may be produced without induction by mucosal immunity. Our findings demonstrate the diversity of the development of IgAN and help to reconsider the onset mechanism of IgAN.

Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflammation and Autoimmunity.

Necroptosis is a form of cell death associated with inflammation; however, the biological consequences of chronic necroptosis are unknown. Necroptosis is mediated by RIPK1, RIPK3, and MLKL kinases but in hematopoietic cells RIPK1 has anti-inflammatory roles and functions to prevent necroptosis. Here we interrogate the consequences of chronic necroptosis on immune homeostasis by deleting Ripk1 in mouse dendritic cells. We demonstrate that deregulated necroptosis results in systemic inflammation, tissue fibrosis, and autoimmunity. We show that inflammation and autoimmunity are prevented upon expression of kinase inactive RIPK1 or deletion of RIPK3 or MLKL. We provide evidence that the inflammation is not driven by microbial ligands, but depends on the release of danger-associated molecular patterns and MyD88-dependent signaling. Importantly, although the inflammation is independent of type I IFN and the nucleic acid sensing TLRs, blocking these pathways rescues the autoimmunity. These mouse genetic studies reveal that chronic necroptosis may underlie human fibrotic and autoimmune disorders.

B Cells Drive Autoimmunity in Mice with CD28-Deficient Regulatory T Cells.

Follicular regulatory T (TFR) cells are a newly defined regulatory T cell (Treg) subset that suppresses follicular helper T cell-mediated B cell responses in the germinal center reaction. The precise costimulatory signal requirements for proper TFR cell differentiation and function are still not known. Using conditional knockout strategies of CD28, we previously demonstrated that loss of CD28 signaling in Tregs caused autoimmunity in mice (termed CD28-ΔTreg mice), characterized by lymphadenopathy, accumulation of activated T cells, and cell-mediated inflammation of the skin and lung. In this study, we show that CD28 signaling is required for TFR cell differentiation. Treg-specific deletion of CD28 caused a reduction in TFR cell numbers and function, which resulted in increased germinal center B cells and Ab production. Moreover, residual CD28-deficient TFR cells showed a diminished suppressive capacity as assessed by their ability to inhibit Ab responses in vitro. Surprisingly, genetic deletion of B cells in CD28-ΔTreg mice prevented the development of lymphadenopathy and CD4+ T cell activation, and autoimmunity that mainly targeted skin and lung tissues. Thus, autoimmunity occurring in mice with CD28-deficient Tregs appears to be driven primarily by loss of TFR cell differentiation and function with resulting B cell-driven inflammation.

IgG4-related disease: features and treatment response in a multi-ethnic cohort in Singapore.

OBJECTIVES: To describe the features and treatment outcomes of IgG4-RD in multi-ethnic patients in Singapore. METHODS: Retrospective study was performed on IgG4-RD patients identified from patient databases in a tertiary hospital. RESULTS: Fourty-two patients (76% male) were included; 79% fulfilled the 2011 comprehensive diagnostic criteria for IgG4-RD for definite IgG4-RD. 81% were Chinese and 19% were Malays. Common initial manifestations included jaundice (52%), abdominal pain (36%) and swollen salivary glands (26%). Only 36% had a history of allergy. 83% had ≥ 1 organ involvement. Erythrocyte sedimentation rate, immunoglobulin E, IgG2 and IgG4 levels were elevated in 84%, 100%, 70% and 44% of patients, respectively. The most common histopathological feature was >10 IgG4+ cells per high power field (66%). 94% (34/36) of patients were treated with moderate to high doses of glucocorticoids, including 17 patients with combination immunosuppressants. Of these, all patients responded to therapy by 3 months. With a median (range) follow-up of 4.1 (0.4-13.8) years, 69% (25/36) needed low dose of glucocorticoids to maintain disease remission. Twenty-six per cent had relapse of disease, of which 82% had disease recurrence in the same organs. CONCLUSIONS: Pancreatitis, lymphoadenopathy and cholangitis were the commonest manifestations in Asians with IgG4-RD. All patients responded to glucocorticoid therapy by 3 months, two-thirds required maintenance therapy with glucocorticoids, and one-quarter developed relapse of disease.

Re-infection of Toxoplasma gondii after HSCT presenting lymphadenopathy resembling recurrence of lymphoma.

Toxoplasma gondii (T. gondii) reactivation is one of the fatal complications after hematopoietic stem cell transplantation (HSCT); however, re-infection has not been reported. Here, we report a case of mycosis fungoides in which cervical lymphadenopathy developed after HSCT. Initially, recurrent lymphoma was suspected. However, biopsy of the lymph node showed typical histology of toxoplasmosis and serology showed re-infection of T. gondii. Toxoplasmosis needs to be differentiated for cases with lymphoadenopthy after HSCT.

Autoimmune Lymphoproliferative Syndrome Masquerading as Posttransplant Lymphoproliferative Disorder.

We present a case of a 2-year-old female presenting with diffuse lymphadenopathy 2 years following orthotopic heart transplant. Initially, she was diagnosed with posttransplant lymphoproliferative disease based on clinical presentation and pathology and she was treated accordingly. Because of persistent lymphadenopathy following the completion of chemotherapy and new onset of autoimmune cytopenias, repeat flow of the lymph node showed an elevated double negative T-cell population prompting evaluation for autoimmune lymphoproliferative syndrome (ALPS). A complete workup was confirmative of a germline Fas mutation consistent with ALPS-FAS. This case emphasizes the importance of considering ALPS-FAS in a patient with lymphadenopathy of unknown cause.

Comparison of IgG4-Related Lymphadenopathy and Multicentric Castleman's Disease: a Retrospective Study.

BACKGROUND: It can be difficult to distinguish between IgG4-related lymphadenopathy and multicentric Castleman's disease (MCD) because these conditions cannot be differentially diagnosed using immunohistochemical staining alone. In this study, we analyzed the clinical features of IgG4-related lymphadenopathy and MCD patients. METHODS: We retrospectively analyzed 27 patients with MCD, including 20 with plasma cell-type (PC-type) and 7 with hyaline vascular (HV) features (mixed-type). An additional 15 patients with IgG4-related lymphadenopathy were enrolled. Clinical data and immune pathological characteristics, including serum interleukin-6 (IL-6) levels, lymph node lesion biopsies, IgG4+/IgG+ expression, and 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) images, were collected. RESULTS: The serum levels of C-reactive protein (CRP), IgA, and IL-6 were significantly elevated in the PC/mixedtype group compared with the IgG4-related lymphadenopathy group (p < 0.05). By contrast, the mean age, eosinophilia, globulin, and serum levels of IgG and IgG4 were significantly higher in the IgG4-RD lymphadenopathy group (all p < 0.05). Thirty percent of patients with IgG4-RD lymphadenopathy had elevated IL-6 levels, and 50% with MCD had elevated serum IgG4 levels. Immunohistochemical studies demonstrated the presence of numerous IgG4+ plasma cells, which accounted for > 40% of IgG4/IgG+ cells in 7 of 27 cases in the PC/mixed-type group. We first found that the mean maximum standard uptake value (SUVmax) was strongly associated with albumin and IL-6 in the IgG4-RD lymphadenopathy group, but not in the MCD group. The number of involved organs, but not the standard uptake value (SUV), helped to distinguish between the two diseases. Most PC/mixed-type group patients responded poorly to glucocorticoids when administered alone or in combination with immunosuppressant drugs. CONCLUSIONS: MCD cannot be differentiated from IgG4-related lymphadenopathy using histology alone. Systematic comparative analysis; clinical and laboratory analyses, especially 18F-FDG-PET/CT; and responses to drug treatment are therefore important parameters for distinguishing between these two diseases.

Acute lymphoblastic leukemia in a patient with IgG4-related disease.

IgG4-related disease (IgG4-RD) is a multi-organ immune-mediated condition characterized by tumor-like lesions, fibrosis, and lymphoplasmacytic infiltration to every organ. Recently, an association between IgG4-RD and malignant tumors has been suggested and IgG4-RD is closely related to the occurrence of malignant hematologic diseases. In this report, we describe a rare complication of acute lymphoblastic leukemia in a patient with IgG4-RD. An 81-year-old Chinese man was diagnosed with the lymphadenopathy associated with IgG4-related disease. The histopathological study revealed multiple plasma cells infiltration and immunostaining for IgG and IgG4 was performed on plasma cells and the IgG/IgG4 ratio was more than 40%. Eight months later, he developed acute lymphoblastic leukemia. It has been suggested that the incidence of malignant hematologic diseases may be high in patients with IgG4-RD and increased Th2 cells and Treg cells cytokines may result in the occurrence of hematologic malignancies. Therefore, the importance of accurate diagnosis and intense medical follow-up should be emphasized. Once the patients develop hematologic malignancies, they need to receive treatment timely.

[Remission of the disease associated/related with immunoglobulin IgG4 accompanied by multiple lymphadenopathy after treatment with rituximab and dexamethasone: a case report]. / Remise "the disease associated/related with immunoglobulin IgG4" provázeného mnohocetnou lymfadenopatií po lécbe rituximabem a dexametazonem: kazuistika.

A disease associated with immunoglobulin IgG4 is a rare unit with very variable symptoms. We describe the course and treatment of the disease in a patient who presented with multiple lymphadenopathy and infiltrates in the area of the retroperitoneum and pelvis and signs of chronic sclerosing pancreatitis. The disease was clinically manifested by a significant loss of weight, but also by a loss of perception of taste and smell. The diagnosis was made based on a high amount of IgG4 expressing plasma cells in the sampled tissue and an increased concentration of immunoglobulins of type IgG and mainly subclass IG4. Rituximab in 475 mg/m2 dose was used in the treatment, the initial four doses of rituximab were administered at 14-day intervals, always with a one-off administration of a 40 mg dose of dexamethasone. According to FDG-PET/CT, only partial remission of the disease was reached after 4 applications of rituximab and dexamethasone. The patient recovered its sense of smell and taste. In another 4 cycles ritu-ximab was administered on day 1 of a 28-day cycle. On days 1 and 15 of the cycle dexamethasone at 40 mg and cyclophosphamide at 600 mg were administered by intravenous infusion. After the completion of 8 cycles of treatment based on rituximab and dexamethasone and with cyclophosphamide added in the second half of the treatment, the control FDG-PET/CT examination proved the complete remission. Before the treatment commencement the concentration of the subclass of immunoglobulin IgG4 was equal to 51.0 g/l, after the completion of the aforementioned treatment it dropped to 3.5 g/l. The patient tolerated the treatment without any adverse effects. Ritu-ximab, dexamethasone and cyclophosphamide induced the complete remission of this disease.Key words: IgG4-associated/releated disease - rituximab.

[CLINICAL AND IMMUNOLOGICAL CRITERIA FOR THE ADVERSE COURSE OF INFECTIOUS MONONUCLEOSIS IN CHILDREN].

The article presents the results of our own studies to determine the criteria for the adverse variants of the course of infectious mononucleosis (IM) in children. The study was conducted in the regional children's infectious clinical hospital in Kharkov. 161 children aged three to fifteen years were under observation with diagnosis of infectious moninucleosis. Out of 161 ill children, 140 (86.9%) had moderate severity of disease, and 21 (13.1%) had severe forms. All children were prescribed standard clinical and laboratory-instrumental examinations. The diagnosis of IM was verified by PCR (detection of VEB DNA in the blood) and ELISA (anti-VEB Ig M and Ig G). In 140 children (86.9%) IM proceeded sharply, smoothly (the first group), in 21 (13.1%) - unfavorably (wave and / or prolonged course) - the second group. The groups were comparable according to age, the severity of the disease and other parameters. All children received therapy according to approved protocols (Order of the Ministry of Health of Ukraine No. 354 of 09.07.2004). Immune status of children was assessed by determining the relative contents of CD3 +, CD4 +, CD8 +, CD16 +, CD19 + blood cells with appropriate monoclonal antibodies, serum IgA, IgM, IgG concentration by Mancini and interleukin (IL) -1ß cytokine response and - 4, tumor necrosis factor (TNF α) is a solid-phase enzyme-linked immunosorbent assay. Based on the results of observations, it was established that the prognostically unfavorable criteria of IМ at the stages of manifestation of disease include: generalized lymphadenopathy involving 5-6 groups of lymph nodes and a significant increasing of them, purulent tonsillitis, marked increasing of size of liver and spleen on the background of anemia, thrombocytopenia, neutropenia and the absence of atypical mononuclears in the complete blood count. There is a depression of the cellular link and an increase in the humoral mechanisms of immune responses in case of development of adverse course of IM.

Disseminated Mycobacterium genavense Infection in Patient with Adult-Onset Immunodeficiency.

We report a case of disseminated Mycobacterium genavense infection resulting from neutralizing anti-interferon-γ autoantibodies in the patient. We identified M. genavense targeting the hsp65 gene in an aspiration specimen of the lymph node. Adult-onset immunodeficiency caused by neutralizing anti-interferon-γ autoantibodies, in addition to HIV infection, can lead to disseminated nontuberculous mycobacterial infection.

Imaging findings of primary immunoglobulin G4-related cervical lymphadenopathy.

PURPOSE: The purpose of the present study was to assess imaging findings of primary immunoglobulin G4 (IgG4)-related cervical lymphadenopathy. METHODS: Five consecutive patients with clinically, serologically, and histopathologically confirmed primary IgG4-related cervical lymphadenopathy without any other organ involvement were included. All patients underwent contrast-enhanced computed tomography (CT), and four underwent 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT. We retrospectively reviewed the images and assessed the number, size, location, central necrosis, perinodal infiltration, penetrating vessels, and maximum standardized uptake values (SUVmax) of the enlarged cervical nodes. RESULTS: Thirteen enlarged cervical nodes measuring larger than 10 mm in minimum diameter were identified. The maximum and minimum diameter of enlarged nodes ranged from 1.2 to 3.2 cm (median, 1.8 cm) and from 1.0 to 1.9 cm (median, 1.2 cm), respectively. Lymphadenopathy was unilateral in all patients, and eight enlarged nodes were located at level IB (62%), one at level II (8%), three at level IV (23%), and one at level V (8%). Central necrosis was not seen in any nodes. Perinodal infiltration was seen in only one node (8%), and penetrating vessels were seen in seven nodes (54%). The median SUVmax of nine nodes was 4.45 (range, 2.08-12.44). CONCLUSION: Eight enlarged nodes (62%) were located in the submandibular region. Central necrosis was not observed in any nodes and perinodal infiltration was observed in one node (8%).

IgG4-related membranous glomerulonephritis and generalized lymphadenopathy without pancreatitis: a case report.

BACKGROUND: IgG4-related disease is a recently described pathologic entity. This is the case of a patient with nephrotic syndrome and lymphadenopathy due to IgG4-related disease. Such a kidney involvement is quite peculiar and has only been described a few times recently. Renal biopsy showed a glomerular involvement with membranous glomerulonephritis in association with a tubulo-interstitial nephropathy. Moreover, the patient was not suffering from pancreatitis. CASE PRESENTATION: The patient is a middle-aged man of Moroccan origin. He has developed recurrent episodes of diffuse lymphadenopathies, renal failure and nephrotic syndrome. Renal biopsies showed membranous glomerulonephritis. DISCUSSION AND CONCLUSION: The diagnostic approach of this atypical presentation is discussed in this case report as well as diagnostic criteria, therapeutic strategies, biomarkers and pathophysiology of IgG4-related disease. IgG4-related membranous glomerulonephritis is a well-established cause of membranous glomerulonephritis. It must be sought after in every patient with a previous diagnosis of IgG4-related disease and in every patient with this histological finding on renal biopsy. Corticoids are still the first-line treatment of IgG4-related disease. New therapeutic strategies are needed to avoid glucocorticoids long term side-effects. Interestingly, the patient was prescribed cyclophosphamide in addition to glucocorticoids for an immune thrombocytopenia. This treatment had a very good impact on his IgG4-related disease.

[A negleted bacteria with a case: Bartonella henselae]. / Bir olgu ile ihmal edilen bir etken: Bartonella henselae.

Bartonella henselae the causative agent of cat scratch disease (CSD), is a gram-negative, coccobacillus, facultative intracellular bacterium CSD usually presents as a clinical form of benign local lymphadenopathy (LAP) but sometimes it may progress to severe life threatening complications. Despite the fact that CSD is known to be a common disease, which is one of the important causes of local LAPs in the world, there are few publications in our country. For the diagnosis, the clinician should suspect for CSD and has to ask to the patient whether there is a story of cat scratch or not. In our country the diagnosis of CSD is usually done by invasive pathological examination instead of simple serological tests. In this report, a 14 years old case with CSD with antibody titers of 1/384 IgM, 1/2048 IgG B.henselae antibody determined by indirect fluorescent antibody (IFA) method in serum and B.henselae positivity by polymerase chain reaction (PCR) from LAP sample of the patient with axillary LAP was presented. Even though molecular techniques have been used for the diagnosis of the previous reported cases, it is the first B.henselae positive case in our country detected with PCR. In the history of the case it was learned that the patient was scratched by a street cat few months ago and the axillary LAP developed 4-5 weeks later. Axillary ultrasonography shawed abscesses with the largest 22 x 44 mm compatible with LAP. No growth was detected in the LAP biopsy specimen culture. Leucocyte count was normal but sedimentation rate (68 mm/h), and C-reactive protein (41.7 mg/L) were higher.Therapy was started with azitromycin 500 mg/day but two weeks later as there was no regression of LAP, considering the development of resistance, the treatment was changed to doxycycline 2 x 100 mg/day and rifampicin 1 x 300 mg/day. As the LAP was in abscess formation and the titers found in IFA was higher than the predictive value of B.henselae antibody titer for endocarditis, the treatment has been extended to four weeks and the patient has been cured. Especially children and adolescents are at very high risk for zoonotic infections transmitted from pets in our country due to the intense immigration to the city from the rural areas and the unconscious and uncontrolled livelihood of friendship with street animals. We should accept that this is not a rare condition, as the cat scratch disease can change from harmless to very serious forms the diagnosis and treatment should be quickly and carefully performed. Currently, serological examinations for Bartonella are rarely done in some certain reference laboratories in our country. The number of these laboratories should be increased or the usage of the tests in these reference laboratories should be at least expanded.

CXCR5 is critically involved in progression of lupus through regulation of B cell and double-negative T cell trafficking.

The recruitment of immune cells to sites of tissue inflammation is orchestrated by chemokine/chemokine receptor networks. Among these, the CXCL13/CXCR5 axis is thought to be involved critically in systemic lupus erythematosus (SLE) and lupus nephritis pathogenesis. Beyond B cell abnormalities, another hallmark of SLE disease is the occurrence of aberrant T cell responses. In particular, double-negative (DN) T cells are expanded in the peripheral blood of patients with SLE and in lupus-prone mice. DN T cells induce immunoglobulin production, secrete proinflammatory cytokines and infiltrate inflamed tissue, including kidneys. We aimed to investigate how CXCR5 deficiency changes immune cell trafficking in murine lupus. We therefore crossed CXCR5(-/-) mice with B6/lpr mice, a well-established murine lupus model. B cell numbers and B cellular immune responses were diminished in CXCR5-deficient B6/lpr mice. In addition, we observed reduced accumulation of DN T cells in spleen and lymph nodes, paralleled by reduced splenomegaly and lymphadenopathy. In-vivo migration assays revealed reduced migration of CXCR5-deficient DN T cells into lymph nodes, and ex-vivo-activated CXCR5-deficient DN T cells failed to infiltrate kidneys of recipients. Moreover, DN T cells and B cells of CXCR5-deficient B6/lpr mice failed to migrate towards CXCL13 in vitro. We propose that CXCR5 is involved critically in B cell trafficking and germinal cell (GC) formation in murine lupus and in guiding pathogenic DN T cells into lymphoid organs and kidneys, and we therefore describe new pathomechanisms for the CXCL13/CXCR5 axis in SLE.

Characterization of Cutaneous Plasmacytosis at Different Disease Stages.

BACKGROUND/AIMS: Cutaneous plasmacytosis is rare and still not well understood. A retrospective study was made of 9 Chinese patients with 1- to 15-year histories of biopsy-proven cutaneous plasmacytosis diagnosed between 2003 and 2015. METHODS: Patient records and archival photographs helped establish the pattern and duration of skin lesions, and skin biopsy specimens provided additional data. RESULTS: The mean age at diagnosis was 46.4 years. Two patients had lesions within 1 year of developing the disease, and 4 had lesions lasting longer than 5 years. One patient had lymphadenopathy of the neck that was later determined to be Castleman disease. Three patients had elevated IgG4 levels; only 2 had increased IgG4+ cells in skin tissues. Flexural accentuation was prominent. Four patients had elevated IgG levels, and 1, with an IgG level >5,000 mg/dL, developed systemic plasmacytosis (later confirmed as Castleman disease). The level of IgG4 subclass was related to disease duration, whereas IgG4+ plasma cells in tissues seemed irrelevant. CONCLUSION: Routine laboratory tests, especially measurement of IgG4 levels, may be useful for following patients with cutaneous plasmacytosis. Because of the retrospective nature of our study, we could only evaluate the results of a single IgG4 test for each patient, but the results pointed to cutaneous plasmacytosis in all 9 patients, who had different stages of the disease. Serial skin biopsies may also be helpful for gauging disease progress. Although IgG4-related disease was not established in any of these patients, long-term follow-up is warranted for all patients.

A rare case of IgG4-related disease: a gastric mass, associated with regional lymphadenopathy.

BACKGROUND: IgG4-related disease (IgG4-RD) is a newly recognized disorder, characterized by massive IgG4+ lymphocyte and plasma cell infiltration, storiform fibrosis, causing enlargement, nodules or thickening of the various organs, simultaneously or metachronously. Involvement of the gastrointestinal tract is very rare and can be presented as a diffuse wall thickening or polyp or mass-like lesion. Up to now, there have been reported only a few cases of isolated gastric IgG4-RD. CASE PRESENTATION: We present an unusual case of IgG4-RD of the stomach with involvement of the regional lymph nodes, clinically manifested as a gastric cancer with related pyloric stenosis. The patient underwent distal gastrectomy, omentectomy and lymph node dissection. The postoperative serum IgG4 level was increased. The diagnosis was confirmed by immunohistochemical study. CONCLUSIONS: In the most of the reported cases there was not sufficient data about the regional lymph nodal status, although the majority of the patients had been operated with presumptive diagnosis of gastric neoplasm. Our case is rare and valuable because it presents a gastric IgG4-related lesion larger than all previously reported in literature, and IgG4-related lymphadenopathy, confirmed histologically, which contributes to better knowledge of the disease.