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.

Hyperimmunoglobulinemia and IgG Subclass Abnormalities in Children With Gaucher Disease.

Gaucher disease (GD) is the most common lysosomal storage disorder, the aim of the current study was to investigate hyperimmunoglobulinemia and abnormalities of serum immunoglobulin G (IgG) subclasses in children with GD and the relation of those findings to the GD phenotype and genotype, duration of enzyme replacement therapy (ERT), and infection frequency. The study included 20 Egyptian children with GD receiving ERT and 20 age-matched and sex-matched healthy children as controls. Serum Ig and serum IgG subclass levels were measured in the children with GD. Serum IgG subclass levels were measured in the control subjects. Hyperimmunoglobulinemia was present in 15 of the 20 (75%) children with GD. In addition, it is found significantly lower IgG2 levels and significantly higher IgG3 levels in the GD group than in the control group (P<0.001 and <0.006, respectively). Patients with 12 infections per year had significantly higher IgG3 levels compared with patients with 6 infections per year (P=0.022). In conclusion, hyperimmunoglobulinemia and IgG subclass abnormalities occur in children with GD who are on ERT and may be related to recurrent infections.

Abdominal aortic aneurysm as an IgG4-related disease.

The objectives of this study were to evaluate patients with aortic abdominal aneurysm (AAA) with regard to immunoglobulin (Ig)G4-related disease (IgG4-RD). IgG4-RD represents a recently defined condition comprised of a collection of disorders characterized by IgG4 hypergammaglobulinemia, the presence of IgG4-positive plasma cells in organs affected with fibrotic or sclerotizing changes and typical histopathological features. It was identified as a possible cause of vasculitis in large vessels. Studies have been published on a possible association between inflammatory aortic or cardiovascular disease and IgG4-RD. We examined 114 patients with AAA requiring surgery in order to identify findings which are characteristic of IgG4-RD. Aneurysm samples from seven patients showed histopathological features consistent with IgG4-RD and the presence of IgG4+ plasma cells. Only two of these seven patients showed elevated IgG4 serum levels higher 1·35 g/l. In five of the patients, the concentration of serum IgG4 was lower than 1·20 g/l, with the number of IgG4+ plasma cells being higher than 50/high-power field. These findings were consistent with AAA being a heterogeneous group of inflammatory diseases with different pathogenesis.

Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Renders B Cells Hyperresponsive to Secondary Infections.

Kaposi's sarcoma-associated herpesvirus (KSHV) induces B cell hyperplasia and neoplasia, such as multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL). To explore KSHV-induced B cell reprogramming in vivo, we expressed the KSHV latency locus, inclusive of all viral microRNAs (miRNAs), in B cells of transgenic mice in the absence of the inhibitory FcγRIIB receptor. The BALB/c strain was chosen as this is the preferred model to study B cell differentiation. The mice developed hyperglobulinemia, plasmacytosis, and B lymphoid hyperplasia. This phenotype was ameliorated by everolimus, which is a rapamycin derivative used for the treatment of mantle cell lymphoma. KSHV latency mice exhibited hyperresponsiveness to the T-dependent (TD) antigen mimic anti-CD40 and increased incidence of pristane-induced inflammation. Lastly, the adaptive immunity against a secondary infection with Zika virus (ZIKV) was markedly enhanced. These phenotypes are consistent with KSHV lowering the activation threshold of latently infected B cells, which may be beneficial in areas of endemicity, where KSHV is acquired in childhood and infections are common.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) establishes latency in B cells and is stringently linked to primary effusion lymphoma (PEL) and the premalignant B cell hyperplasia multicentric Castleman's disease (MCD). To investigate potential genetic background effects, we expressed the KSHV miRNAs in BALB/c transgenic mice. BALB/c mice are the preferred strain for B cell hybridoma development because of their propensity to develop predictable B cell responses to antigen. The BALB/c latency mice exhibited a higher incidence of B cell hyperplasia as well as sustained hyperglobulinemia. The development of neutralizing antibodies against ZIKV was augmented in BALB/c latency mice. Hyperglobulinemia was dampened by everolimus, a derivative of rapamycin, suggesting a role for mTOR inhibitors in managing immune activation, which is hallmark of KSHV infection as well as HIV infection.

Natural History and Predictors of Progression to Sjögren's Syndrome Among Participants of the Sjögren's International Collaborative Clinical Alliance Registry.

OBJECTIVE: To explore changes in the phenotypic features of Sjögren's syndrome (SS), and in SS status among participants in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry over a 2-3-year interval. METHODS: All participants in the SICCA registry who were found to have any objective measures of salivary hypofunction, dry eye, focal lymphocytic sialadenitis in minor salivary gland biopsy, or anti-SSA/SSB antibodies were recalled over a window of 2 to 3 years after their baseline examinations to repeat all clinical examinations and specimen collections to determine whether there was any change in phenotypic features and in SS status. RESULTS: As of September 15, 2013, a total of 3,514 participants had enrolled in SICCA, and among 3,310 eligible, 771 presented for a followup visit. Among participants found to have SS using the 2012 American College of Rheumatology (ACR) classification criteria, 93% again met the criteria after 2 to 3 years, and this proportion was 89% when using the 2016 ACR/European League Against Rheumatism (EULAR) criteria. Among those who did not meet ACR or ACR/EULAR criteria at baseline, 9% and 8%, respectively, had progressed and met them at followup. Those with hypergammaglobulinemia and hypocomplementemia at study entry were, respectively, 4 and 6 times more likely to progress to SS by ACR criteria than those without these characteristics (95% confidence interval 1.5-10.1 and 1.8-20.4, respectively). CONCLUSION: While there was stability over a 2-3-year period of both individual phenotypic features of SS and of SS status, hypergammaglobulinemia and hypocomplementemia at study entry were predictive of progression to SS.

Acute cardiac disease in a patient with hyper-IgE syndrome.

SUMMARY: We describe the case of a 24-year-old male with hyper-IgE syndrome (HIES) which was diagnosed at 4 years of age and died from a very rare cardiac complication. He had typical clinical and laboratory manifestations of HIES, including total serum IgE as high as > 100,000 IU/mL. Stem cell transplantation was not available. During the 20-year follow-up, he suffered numerous various infections of the skin and deep organs, partial lung resection, as well as multiple bone fractures. At age 24, he developed acute decompensated heart failure associated with elevated serum troponin I and brain natriuretic protein. Two-dimensional echocardiogram revealed global hypokinesis of the left ventricle with estimated ejection fraction 20-25%, and catheterization revealed ectasia of multiple coronary arteries. Endomyocardial biopsy showed lymphocytic myocarditis, focal necrosis, mild fibrosis, and myxoid degeneration, but cultures were negative. The patient improved on corticosteroid therapy and was discharged on heart failure therapy and external defibrillator. Six weeks later, he developed supraventricular tachycardia and persistent global hypokinesis and was treated with amiodarone. A trial of intravenous immunoglobulin was initiated and was repeated as outpatient every four weeks for four times. However, his cardiac function did not improve and he developed severe hypotension and pulseless electrical activity arrest. Resuscitation was unsuccessful. To the best of our knowledge, this is the first reported case of HIES complicated with lymphocytic myocarditis. Both immunologists and cardiologists need to be aware of such a complication and practice caution in using immunosuppressants when the patient's immune status is markedly compromised.

MST1 deficiency promotes B cell responses by CD4+ T cell-derived IL-4, resulting in hypergammaglobulinemia.

MST1 deficiency causes T and B cell lymphopenia, resulting in combined immunodeficiency. However, MST1-deficient patients also exhibit autoimmune-like symptoms such as hypergammaglobulinemia and autoantibody production. Recent studies have shown that the autoimmune responses observed in MST1-deficient patients were most likely attributable to defective regulatory T (Treg) cells instead of intrinsic signals in MST1-lacking B cells. Nevertheless, it is not determined how MST1 deficiency in T cells breaks B cell tolerance and causes systemic autoimmune-like phenotypes. In this study, we confirmed that Mst1-/- mice developed hypergammaglobulinemia associated with increased levels of IgG, IgA, and IgE. We also showed that uncontrolled B cell responses were resulted from the IL-4-rich environment created by CD4+ T cells. Defective MST1-FOXO1 signaling down-regulated Treg cells, resulting in the collapse of immune tolerance where the populations of Th2 and T follicular helper cells expanded. In conclusion, we suggest that MST1 acts as a molecular brake to maintain immune tolerance by regulating T cell-mediated B cell activation.

IgG4-related disease in autoimmune lymphoproliferative syndrome.

A patient with autoimmune lymphoproliferative disorder (ALPS) developed IgG4-related disease. In retrospect, he had high levels of serum IgG4 for several years prior to presenting with IgG4-related pancreatitis. These high IgG4 levels were masked by hypergammaglobulinemia, a common feature of ALPS. We next screened 18 ALPS patients; four of them displayed increased levels of IgG4. Hence, IgG4-related disease should be considered in ALPS patients, especially in those manifesting lymphocytic organ infiltration or excessive hypergammaglobulinaemia. Screening of IgG4-related disease patients for ALPS-associated mutations would provide further information on whether this disease could be a late-onset atypical presentation of ALPS.

IgG4-related disease manifesting as pericarditis with elevated adenosine deaminase and IL-10 levels in pericardial fluid.

A 78-year-old female with massive pericardial effusion fulfilled diagnostic criteria for immunoglobulin G4 (IgG4)-related disease. Although her adenosine deaminase (ADA) level in the pericardial effusion was high, all the tests for tuberculosis infection were negative. Immunostaining of the pericardium biopsy specimen revealed remarkably increased IgG4-positive cells. This is the first report describing IgG4-related pericarditis with elevated ADA level. We also demonstrate the elevated interleukin-10 (IL-10) level in pericardial fluid and IL-10-producing T-cells in the pericardium.

Clinical relevance of RORγ positive and negative subsets of CD161+CD4+ T cells in primary Sjögren's syndrome.

OBJECTIVE: The relevance of the Th17 pathway in primary SS (pSS) is unclear. Published studies have relied on restimulating circulating CD161+ T cells in vitro for quantitation of IL-17-producing cells. While CD161 marks all IL-17+ T cells, it is also expressed by other Th subsets. The aim of this study was to directly analyse retinoic acid receptor-related orphan nuclear receptor (ROR)-γ expressing and non-expressing subsets of CD161+ T cells to determine the relevance of the Th17 pathway in pSS. METHODS: We quantitated the frequencies of both CD161- and RORγ-expressing T cells by comparative flow cytometry in peripheral blood mononuclear cells from a well-stratified cohort of pSS patients and control subjects. We also analysed the expression of antigen D-related HLA (HLA-DR) and CD161 in labial salivary glands from nine subjects undergoing a diagnostic biopsy. RESULTS: While the frequencies of both RORγ+ and RORγ- subsets of CD161+ CD4+ T cells were increased in peripheral blood from pSS patients, the increase in the RORγ+ subset positively correlated with humoral manifestations of the disease (anti-SSA/SSB autoantibodies and hypergammaglobulinaemia), but not with disease activity, and vice versa for the RORγ- subset. An increased frequency of HLA-DR+ CD161+CD4+ T cells was observed in labial salivary gland biopsies from pSS patients, suggesting chronic activation of CD161+CD4+ T cells in the target tissue of the disease. CONCLUSION: In addition to pointing to CD161 as a marker of a pathogenic subset of CD4+ T cells in pSS patients, our data indicate that even though the RORγ+ (Th17) CD161+ subset might contribute to humoral manifestations of the disease, the RORγ- (non-Th17) CD161+ subset is the one associated with disease activity in pSS patients.

Rapid Fatal Acute Peripheral T-Cell Lymphoma Associated With IgG Plasma Cell Leukemia and IgA Hypergammaglobulinemia.

Simultaneous occurrence of T-cell and B-cell neoplasms is rare, and etiologic relationships between these 2 malignancies are poorly understood. We describe the case of a 66-year-old woman who was admitted to the hospital because of fever, hemoptysis, lymphadenopathy, and skin rash. Enlarged lymph nodes in axillary, pectoral, paratracheal, and periportal regions as well as slight hepatomegaly and splenomegaly were confirmed. A peripheral blood smear revealed rouleaux formation and numerous circulating plasma cells, with plasmacytoid lymphocytes. Immunofixation-electrophoresis detected a monoclonal band defined as immunoglobulin (IgG)-lambda light chains with broad-band polyclonal IgA. The patient died from abrupt splenic rupture before diagnostic work-up was finished. Postmortem examination revealed infiltration of atypical lymphoid cells exhibiting high proliferative activity admixed with typical and atypical plasma cells in several organs. Thus, plasma cell leukemia (IgG-lambda) as a rare and aggressive variant of plasma cell myeloma in the present case was associated with aggressive peripheral T-cell lymphoma and polyclonal (IgA) plasmacytosis.

Disruption of Splenic Lymphoid Tissue and Plasmacytosis in Canine Visceral Leishmaniasis: Changes in Homing and Survival of Plasma Cells.

Visceral leishmaniasis (VL) is a disease caused by Leishmania infantum, which is transmitted by phlebotomine sandflies. Dogs are the main urban reservoir of this parasite and the disease presents similar characteristics in both humans and dogs. In this paper, we investigated the potential pathways involved in plasma cell replacement of normal cell populations in the spleen, with respect to disease severity in dogs from an endemic area for visceral leishmaniasis. To this end, canine spleen samples were grouped into three categories: TYPE1SC- (non-infected dogs or without active infection with organized white pulp), TYPE1SC+ (infected dogs with organized white pulp) or TYPE3SC+ (infected animals with disorganized white pulp). We analyzed the distribution of different plasma cell isotypes (IgA, IgG and IgM) in the spleen. The expression of cytokines and chemokines involved in plasma cell homing and survival were assessed by real time RT-PCR. Polyclonal B cell activation and hypergammaglobulinemia were also evaluated. The proportion of animals with moderate or intense plasmacytosis was higher in the TYPE3SC+ group than in the other groups (Fisher test, P<0.05). This was mainly due to a higher density of IgG+ plasma cells in the red pulp of this group. The albumin/globulin ratio was lower in the TYPE3SC+ animals than in the TYPE1SC- or TYPE1SC+ animals, which evidences VL-associated dysproteinemia. Interestingly, TYPE3SC+ animals showed increased expression of the BAFF and APRIL cytokines, as well as chemokine CXCL12. Aberrant expression of BAFF, APRIL and CXCL12, together with amplified extrafollicular B cell activation, lead to plasma cell homing and the extended survival of these cells in the splenic red pulp compartment. These changes in the distribution of immunocompetent cells in the spleen may contribute to the progression of VL, and impair the spleen's ability to protect against blood borne pathogens.

Brief Report: Patients With Primary Sjögren's Syndrome Who Are Positive for Autoantibodies to Tripartite Motif-Containing Protein 38 Show Greater Disease Severity.

OBJECTIVE: Autoantibodies reactive with Ro52 (tripartite motif-containing protein 21 [TRIM21]) are detected in 70% of patients with primary Sjögren's syndrome (SS). TRIM21 belongs to a 34-member C-IV family of TRIM proteins. Although autoantibodies against other TRIM proteins within the C-IV family have been detected in the sera of patients with primary SS, their clinical relevance remains unclear. This study was undertaken to investigate the frequency of anti-TRIM38 in patients with primary SS and evaluate its association with various clinical measures of the disease. METHODS: Serum samples from patients with primary SS (n = 235) and controls (n = 50) were analyzed for reactivity with in vitro-transcribed and -translated (35) S-methionine-labeled TRIM38 protein. The associations of anti-TRIM38 with various laboratory and clinical measures of primary SS were evaluated. Reactivity of anti-TRIM38 with different structural domains of TRIM38 was analyzed. Affinity-purified anti-TRIM38 antibodies were used to immunoprecipitate TRIM21. RESULTS: TRIM38-reactive autoantibodies were detected in the sera of 24 of the 235 patients with primary SS and 2 of the 50 controls. Anti-TRIM38 positivity was significantly associated with the presence of anti-Ro60, anti-Ro52, anti-La, rheumatoid factor, and hypergammaglobulinemia. Clinically, anti-TRIM38 was associated with significantly higher ocular surface staining scores, lower Schirmer's test scores, and minor labial salivary gland biopsy focus scores of ≥3.0. Anti-TRIM38 antibodies mainly recognized the cortactin-binding protein 2 (CortBP-2; amino acids 128-238) and the B30.2/SPRY (amino acids 268-465) domains on TRIM38. Affinity-purified antibodies to TRIM38-CortBP-2 and TRIM38-B30.2/SPRY domains reacted with TRIM21. CONCLUSION: Our data demonstrate that anti-TRIM38 specificity arising in a subset of patients with primary SS is associated with increased severity of the disease.

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.

Low marginal zone-like B lymphocytes and natural antibodies characterize skewed B-lymphocyte subpopulations in del22q11 DiGeorge patients.

PURPOSE: Patients with DiGeorge syndrome suffer from T-lymphopenia. T-cells are important for the maturation and regulation of B-cell function. Our aim was to characterize the B-cell compartment in DiGeorge syndrome patients. METHODS: B-cell subset phenotypization using flow cytometry. Serum BAFF (B-cell activating factor) and serum anti-alpha-galactosyl IgM measurement using ELISA. Serum IgG measurement using nephelometry. RESULTS: We observed a significantly increased number of naïve B-cells and decreased number of switched memory B-cells in DiGeorge patients. Furthermore, we observed increased BAFF levels and a trend toward hypergammaglobulinemia later in life. Surprisingly, we detected a decrease in marginal zone-like (MZ-like) B-cells and natural antibodies in DiGeorge patients. CONCLUSION: The maturation of B-cells is impaired in DiGeorge patients, with high naïve and low switched memory B-cell numbers being observed. There is a clear trend toward hypergammaglobulinemia later in life, coupled with increased serum BAFF levels. Surprisingly, the T-independent humoral response is also impaired, with low numbers of MZ-like B-cell and low levels of anti-alpha-galactosyl IgM natural antibodies being detected.

The injured liver induces hyperimmunoglobulinemia by failing to dispose of antigens and endotoxins in the portal system.

Hyperimmunoglobulinemia is frequently observed in patients with chronic liver diseases. However, the exact mechanism underlying the high level of antibody formation is not fully understood. In our study, we provide evidence for the functional role of the liver and the stimulation of plasma cell proliferation in hyperimmunoglobulinemia. We collected sera from patients with chronic liver diseases, and the level of serum immunoglobulins in patients was examined; this was also investigated in animal models of liver cirrhosis and hepatocellular carcinoma. An end-to-side microsurgical portacaval shunt was used to mimic liver dysfunction in rats. We used portal vein serum and inferior vena cava serum to immunize healthy rats and mice in order to confirm the function of the healthy liver in disposing of antigens and endotoxins from the gut. For the analysis of the state of plasma cell activation, plasma cells from mice were stained with PE-conjugated anti-CD138 and FITC-conjugated anti-BrdU for flow cytometry analysis. Hyperimmunoglobulinemia was observed both in patients with chronic liver diseases and in related animal models, and high plasma LPS levels were also observed. There was a significant increase in the activation and proliferation of plasma cell in mice immunized with antigens or LPS-positive serum compared with controls that were immunized with antigens and LPS-negative serum. We confirmed that the healthy liver plays an important role in disposing of antigens and endotoxins derived from the gut. Hyperimmunoglobulinemia in chronic liver diseases mainly arises due to the collateral circulation secondary to portal hypertension, gut antigens and endotoxins that bypass the liver and reach the antibody-producing cells.

Antibody effector functions mediated by Fcγ-receptors are compromised during persistent viral infection.

T cell dysfunction is well documented during chronic viral infections but little is known about functional abnormalities in humoral immunity. Here we report that mice persistently infected with lymphocytic choriomeningitis virus (LCMV) exhibit a severe defect in Fcγ-receptor (FcγR)-mediated antibody effector functions. Using transgenic mice expressing human CD20, we found that chronic LCMV infection impaired the depletion of B cells with rituximab, an anti-CD20 antibody widely used for the treatment of B cell lymphomas. In addition, FcγR-dependent activation of dendritic cells by agonistic anti-CD40 antibody was compromised in chronically infected mice. These defects were due to viral antigen-antibody complexes and not the chronic infection per se, because FcγR-mediated effector functions were normal in persistently infected mice that lacked LCMV-specific antibodies. Our findings have implications for the therapeutic use of antibodies and suggest that high levels of pre-existing immune complexes could limit the effectiveness of antibody therapy in humans.