Clinical characteristics and risk factors of Helicobacter pylori infection-associated Sjogren's syndrome.

OBJECTIVE: Although infectious pathogens are predominant factors for inducing and maintaining immune system disorders, there exist few reports establishing the significant correlation between Helicobacter pylori (H. pylori) infection and Sjogren's syndrome. This study aims to demonstrate the correlation between Sjogren's syndrome and H. pylori infection in patients, highlighting various clinical characteristics and risk factors. METHODS: A single-center retrospective observational study was conducted in patients (n = 224) admitted from January 1, 2012, to February 10, 2021, in the First Affiliated Hospital of Wenzhou Medical University (Wenzhou, China). All the recruited subjects with Sjogren's syndrome and H. pylori infection were only included by validating the available medical records online. RESULTS: In this study, a total of 224 patients from January 1, 2012, to February 10, 2021, were diagnosed with Sjogren's syndrome. Among them, 94 patients (41.96%) with Sjogren's syndrome were infected with H. pylori. Accordingly, the clinical manifestations, serological and immunological characteristics, as well as gastroscopic biopsy outcomes of the recruited patients with primary Sjogren's syndrome (pSS) were reported. The multivariable analysis of the dry syndrome patients infected with H. pylori displayed hypergammaglobulinemia (odds ratio [OR], 0.354; 95% confidence interval [CI], 0.189-0.663), total cholesterol (OR, 1.158; 95% CI, 0.856-1.550), hypertension (OR, 0.227; 95% CI, 0.114-0.455), Female sex (OR, 5.778; 95% CI, 1.458-22.9), anti-SSA/Ro60 positive (OR, 2.384; 95% CI, 233-4.645), γ-GT (OR, 0.99; 95% CI, 0.99-1.00) and alkaline phosphatase (ALP, OR, 1.00; 95% CI, 0.99-1.00) levels. CONCLUSION: Together, our findings demonstrated that hypergammaglobulinemia could be the independent risk factors of H. pylori infection in patients with Sjogren's syndrome, requiring the physician's advice in the future.

Clinical report and predictors of sequelae of 319 cases of pediatric bacterial osteomyelitis.

Pediatric osteomyelitis is an insidious disease that can lead to permanent sequelae, the management of which still relies on lengthy intravenous antibiotic therapy. The purpose of this study is to report and describe the clinical course and outcome of pediatric bacterial osteomyelitis in our experience. We reported the clinical, diagnostic, and treatment characteristics of all cases of osteomyelitis in children younger than 18 years of age who were hospitalized between January 2010 and December 2021 at the Bambino Gesù Children's Hospital in Rome, Italy, we compared patients with and without complications at follow-up, to identify any predictive factor for sequelae. The study sample included 319 cases of pediatric bacterial osteomyelitis. The median age was 7.77 years. Males (60.8%) were more affected than females. The most affected bones were the femur, tibia, and spine. Etiology was identified in 40.1% of cases, with S.aureus as the most common causative agent. Sequelae were reported in 43 cases (13.5%). The main predictors of sequelae were sepsis on admission and hypergammaglobulinemia. Our results show that a severe presentation with sepsis and hypergammaglobulinemia on admission may be associated with a higher frequency of late sequelae. Early recognition and aggressive treatment of this subgroup of patients may lead to a reduction in complications.

Inflammatory diseases in hematology: a review.

Hematopoietic cells are instrumental in generating and propagating protective inflammatory responses to infection or injury. However, excessive inflammation contributes to many diseases of the blood, bone marrow, and lymphatic system. We review three clinical categories of hematological inflammatory diseases in which recent clinical and translational advances have been made. The first category is monogenic inflammatory diseases. Genotype-driven research has revealed that previously mysterious diseases with protean manifestations are characterized by mutations that may be germline (e.g., deficiency of ADA2 or GATA2 deficiency) or somatic [e.g., vacuoles, enzyme E1, X-linked, autoinflammatory, somatic (VEXAS) syndrome]. The second category is the cytokine storm syndromes, including hemophagocytic lymphohistiocytosis, and Castleman disease. Cytokine storm syndromes are characterized by excessive production of inflammatory cytokines including interleukin-6 and interferon-γ, causing end-organ damage and high mortality. Finally, we review disorders associated with monoclonal and polyclonal hypergammaglobulinemia. The serum protein electrophoresis (SPEP) is typically ordered to screen for common diseases such as myeloma and humoral immunodeficiency. However, monoclonal and polyclonal hypergammaglobulinemia on SPEP can also provide important information in rare inflammatory diseases. For example, the autoinflammatory disease Schnitzler syndrome is notoriously difficult to diagnose. Although this orphan disease has eluded precise genetic or histological characterization, the presence of a monoclonal paraprotein, typically IgM, is an obligate diagnostic criterion. Likewise, polyclonal hypergammaglobulinemia may be an important early, noninvasive diagnostic clue for patients presenting with rare neoplastic diseases such as Rosai-Dorfman disease and angioimmunoblastic T-cell lymphoma. Applying these three categories to patients with unexplained inflammatory syndromes can facilitate the diagnosis of rare and underrecognized diseases.

IL-2 contributes to cirrhosis-associated immune dysfunction by impairing follicular T helper cells in advanced cirrhosis.

BACKGROUND & AIMS: Patients with decompensated cirrhosis suffer from recurrent infections and inadequate responses to prophylactic vaccinations. However, many patients present with hypergammaglobulinemia (HGG), indicating a sustained ability to generate antibody responses. As follicular T helper (Tfh) cells are central facilitators of humoral immunity, we hypothesized that Tfh cell responses may be altered in advanced liver disease and we aimed to identify the mechanisms underlying any such alterations. METHODS: Tfh, regulatory T (Treg) cells, B cells, circulating cytokines and immunoglobulins were analyzed in cohorts of patients with compensated (n = 37) and decompensated cirrhosis (n = 82) and in non-cirrhotic controls (n = 45). Intrahepatic T cells were analyzed in 8 decompensated patients. The influence of IL-2 on Tfh cell function was evaluated in vitro, including Tfh cell cloning and T cell-B cell co-cultures with clones and primary tonsil-derived Tfh cells. RESULTS: Tfh cell frequencies were reduced in patients with decompensated cirrhosis, with phenotypic signatures indicative of increased IL-2 signaling. Soluble IL-2 receptor (sCD25) was elevated in these patients and CD4 T cells were more responsive to IL-2 signaling, as characterized by STAT5 phosphorylation. IL-2 exposure in vitro diminished the Tfh phenotype and resulted in impaired Tfh helper function in co-culture experiments with naïve B cells. Tfh cells were barely detectable in cirrhotic livers. IL-2 signatures on Tfh cells in decompensated patients correlated with immunoglobulin levels, which were found to be associated with improved survival. CONCLUSIONS: Tfh cell impairment represents a previously underestimated feature of cirrhosis-associated immune dysfunction that is driven by IL-2. The presence of HGG in decompensated patients predicts an intact Tfh cell compartment and is associated with a favorable outcome. LAY SUMMARY: Patients with advanced cirrhosis often fail to generate protective immunity after prophylactic vaccinations and suffer from recurring infections that are associated with high mortality. Follicular T helper (Tfh) cells are specialized CD4 T cells that enable the emergence of antibody responses against microbial pathogens. This report demonstrates that Tfh cells are impaired in patients with advanced cirrhosis due to interleukin-2 signaling, a cytokine that is known to impair the generation of Tfh cells.

Telbivudine on IgG-associated hypergammaglobulinemia and TGF-ß1 hyperactivity in hepatitis B virus-related liver cirrhosis.

As debate rumbles on about whether anti-hepatitis B virus (HBV) nucleos(t)ide analogue treatments modulate host immune system during end-stage liver diseases, we studied effects of two potent anti-HBV agents, telbivudine or entecavir, on humoral immune activities including cytokine secretion, immunoglobulin production, and IgG-Fc agalactosylation, which is known to induce proinflammatory responses, in liver cirrhosis. Serum IgG-Fc N-glycan structures in patients with HBV-related liver cirrhosis, who had received either telbivudine treatment or entecavir treatment for at least 48 weeks were analyzed using liquid chromatography tandem-mass spectrometry. Levels of cytokines and each immunoglobulin isotype were measured using enzyme-linked immunosorbent assays. Results showed that 48 weeks of entecavir treatment caused HBV DNA loss, alanine aminotransferase normalization, and an amelioration of hypergammaglobulinemia in cirrhotic patients; however, telbivudine treatment, though possessing similar efficacies on HBV suppression and an improvement in liver inflammation to entecavir treatment, did not mitigate IgG-related hypergammaglobulinemia. Levels of IgG and transforming growth factor (TGF)-ß1 in sera of the cirrhotic patients before and during treatment were positively correlated. In vitro assays revealed that telbivudine treatment induced TGF-ß1 expression in human macrophagic cells. Moreover, recombinant TGF-ß1 treatment stimulated cell proliferation and IgG overproduction in human IgG-producing B cell lines. Finally, we found that telbivudine treatment enhanced the proportion of serum IgG-Fc agalactosylation in cirrhotic patients, which was associated with enhanced levels of TGF-ß1 and IgG. In conclusion, telbivudine therapy was associated with TGF-ß1 hyperactivity, IgG-related hypergammaglobulinemia, and IgG-Fc agalactosylation in HBV-related liver cirrhosis.

Hypergammaglobulinemia and Impaired Transplacental Transfer of Respiratory Syncytial Virus Antibody in Papua New Guinea.

BACKGROUND: Passively-acquired respiratory syncytial virus (RSV) neutralizing antibody (Ab) can protect against RSV-associated lower respiratory tract illness. Maternal RSV immunization is, therefore, an attractive strategy for protection of very young infants. Vaccines for this purpose are currently being evaluated in clinical trials, but conditions such as preterm birth, placental malaria, maternal hypergammaglobulinemia and HIV infection might threaten this strategy. Each has been shown to impair transplacental Ab transfer for a variety of pathogens, but RSV-specific data are limited. Work in The Gambia demonstrated that placental malaria impaired transplacental transfer of RSV Ab, but a subsequent study in malaria-endemic Papua New Guinea (PNG) indicated that such associations may have been confounded by hypergammaglobulinemia (IgG > 1700 mg/dL). METHODS: Here we confirm and extend those findings by measuring RSV neutralizing Ab and maternal IgG in sera from a larger cohort of 325 mother/infant pairs in PNG, and demonstrate the applicability of a high-throughput assay for assessment of neutralizing Ab. RESULTS: One-third of mother-infant pairs demonstrated impaired RSV Ab transfer. Infants of hypergammaglobulinemic women were more likely to have both impaired transfer [cord-to-maternal titer ratio <1.0, adjusted odds ratio (OR): 3.36 (95% confidence interval: 1.81-6.30)] and the lowest RSV cord titers [adjusted OR: 5.09 (95% confidence interval: 1.95-13.32, P < 0.001)], but neither outcome was associated with placental malaria. CONCLUSIONS: Once maternal RSV vaccines become available, successful implementation will require clear understanding and mitigation of factors that can impair passive protection, necessitating epidemiologic studies of such relationships ahead of vaccine availability. This study underscores the need to focus on hypergammaglobulinemia as a condition of importance.

Acute hyperviscosity: syndromes and management.

Plasma hyperviscosity is a rare complication of both monoclonal and polyclonal disorders associated with elevation of immunoglobulins. Asymptomatic patients with an elevation in the serum viscosity do not require plasma exchange, and the majority will have other indications for therapeutic intervention. For patients with hemorrhagic or central nervous system manifestations, plasma exchange is the therapy of choice and is relatively safe. Viscosity measurements are not required to initiate therapy if the index of suspicion is high and the clinical presentation is typical. However, patients should have a sample sent for confirmation of the diagnosis. Whole-blood hyperviscosity is seen in patients with extreme elevation of the red cell and white cell count. Phlebotomy of patients with primary and secondary elevation of the red cell count is a well-established therapy.

IgG4-related disease coexisting with autoimmune haemolytic anaemia.

An 85-year-old man presented with a pale appearance and generalised pruritic papules. Laboratory investigations disclosed eosinophilia, autoimmune haemolytic anaemia, mixed hyperbilirubinaemia, cholestasis and elevated serum IgG4 levels. Abdominal sonography and CT showed progressive dilatation of biliary trees, with diffuse pancreatic enlargement and a subtle capsule-like low-density rim around the pancreatic head and body. Endoscopic retrograde cholangiopancreatography found no stone-related biliary obstruction, while endoscopic transpapillary biopsy demonstrated chronic inflammation only. Nevertheless, the diagnosis of IgG4-related disease with coexisting autoimmune haemolytic anaemia was presumed. The clinical picture and laboratory abnormalities improved after administration of moderate dose of methylprednisolone.

Serum Levels of IL-33 and Correlation with IL-4, IL-17A, and Hypergammaglobulinemia in Patients with Autoimmune Hepatitis.

This study investigated the role of IL-33 in the pathogenesis of autoimmune hepatitis (AIH). The levels of IL-33/sST2 and Th1/Th2/Th17-type cytokines were determined by enzyme-linked immunosorbent assay in serum samples obtained from 30 AIH patients and 20 healthy controls (HCs). In addition, a murine model of experimental AIH (EAIH) was established to investigate the role of IL-33 in disease progression. The serum levels of IL-33, sST2, Th17 cytokines (IL-17A), Th1 cytokines (IFN-γ, TNF-α), and Th2 cytokines (IL-4) were significantly elevated in AIH patients compared to HCs. Following immunosuppression therapy, serum levels of IL-33 and sST2 were significantly decreased. Additionally, the serum levels of IL-33 in AIH patients were correlated positively with markers of hypergammaglobulinemia (IgG, IgM, and IgA) and liver injury (γ-GT/ALP). Also, the serum levels of IL-33 in AIH patients were correlated positively with proinflammatory cytokine levels (IL-17A and IL-4). Interestingly, treatment of EAIH mice with a specific IL-33 neutralizing antibody significantly reversed the increasing trend in serum ALT/AST and inhibited the production of the type 2 (IL-4) and type 17 cytokines (IL-17) but not the type 1 cytokine (IFN-γ). Our findings highlight the possible role of the IL-33/sST2 axis in the progression of AIH, opening a new door for developing a novel therapeutic strategy for AIH.

Urological manifestations of the disease related to immunoglobulin G4. / Manifestaciones urológicas de la enfermedad relacionada con la inmunoglobulina G4

Immunoglobulin G4 related disease (IgG4-RD) is a fibro-inflammatory disease of unknown etiology, characterized by lesions in the form of tumors, elevated serum IgG4 levels, plasma cells with significant IgG4 infiltration, accompanied by phlebitis obliterans and fibrosis. This disease usually has multiorgan disease, including pancreas, biliary tract, salivary glands, peri orbital tissues, kidneys, lungs, lymph nodes and retro peritoneum. IgG4-RD mainly affects men with a predominance of age by young adults until old age. The clinical manifestations of IgG4-RD, depend mainly on the organs affected and the response to steroids. His forecast is not yet clear. Within the affected urogenital organs can be observed kidney, retroperitoneum, ureter, bladder, urachus, testis/epididymis, paratesticular region, prostate and urethra.

La enfermedad relacionada con la inmunoglobulina G4 (ER-IgG4) es una enfermedad fibroinflamatoria de etiología desconocida, la cual se caracteriza por presentar lesiones en forma de tumoraciones, concentraciones séricas aumentadas de IgG4 y células plasmáticas con una infiltración importante de IgG4, junto con flebitis obliterante y fibrosis. Esta enfermedad suele tener afección multiorgánica, incluyendo el páncreas, el tracto biliar, las glándulas salivares, los tejidos periorbitarios, los riñones, los pulmones, los ganglios linfáticos y el retroperitoneo. La ER-IgG4 afecta principalmente a hombres, con un predominio de edad por los adultos jóvenes y hasta la vejez. Las manifestaciones clínicas de la ER-IgG4 dependen principalmente de los órganos afectados y de la respuesta a los esteroides. Su pronóstico aún no es del todo claro. Dentro de los órganos urogenitales afectados pueden incluirse el riñón, el retroperitoneo, el uréter, la vejiga, el uraco, el testículo/epidídimo, la región paratesticular, la próstata y la uretra.

Gastrointestinal histoplasmosis ileal stricture successfully treated with through-the-scope balloon dilation in a patient with hyperimmunoglobulin M syndrome.

Gastrointestinal histoplasmosis is common in patients with disseminated disease affecting both immunocompetent and immunocompromised patients. However, it is often unrecognized due to a lack of specific signs and symptoms. It has only rarely been reported to cause small bowel obstruction, during which surgical treatment was nearly always necessary. Little is known about the usefulness of endoscopic therapy in gastrointestinal histoplasmosis associated strictures. We report the case of a 32-year-old man with a history of hyperimmunoglobulin M syndrome who presented with small bowel obstruction secondary to disseminated gastrointestinal histoplasmosis. Treatment was successful with a through-the-scope balloon dilator in combination with medical therapy. This report adds to the limited data available on the benefit of endoscopic therapy in infectious strictures, particularly gastrointestinal histoplasmosis.

Immunoglobulinopathies in patients with angioimmunoblastic T-cell lymphoma.

AIM: The aim of the study was to characterize quantitative and qualitative immunoglobulinopathies in patients with AITL at the onset of the disease. MATERIALS AND METHODS: 55 patients with newly diagnosed AITL were enrolled in the study, the male/female ratio was 30/25; median age was 61 (29-81) years. Diagnosis was based on standard WHO criteria. Immunochemical studies of blood serum included serum protein electrophoresis/immunofixation, nephelometric quantification of total immunoglobulins, serum free light chain assay. RESULTS: Quantitative and qualitative immunoglobulinopathies were determined in 49 (89,1%) of 55 pts. Quantitative immunoglobulinopathies were revealed in 47 (85.5%) of 55 cases, qualitative - in 14 (25,5%). Combination quantitative and qualitative immunoglobulinopathies was observed in 12 (21,8%) of 55 pts. The detected immunoglobulinopathies were divided into 4 groups: polyclonal hypergammaglobulinaemia, hypogammaglobulinaemia, oligoclonal gammapathy, and monoclonal gammapathy. Polyclonal hypergammaglobulinaemia was marked in 41 (74.5%) of 55 pts, elevated level of IgG was determined in 27 (49,15%) of 55 cases, IgM - in 18 (32,7%) and IgA - in 21 (38.2%). Interestingly, polyclonal IgE hypergammaglobulinaemia was detected in 12 (48,0%) of 25 cases of performed studies. Hypogammaglobulinaemia was detected in 8 (14,5%) of 55 cases. Oligoclonal gammapathy was determined in 4 (7.3%) of 55 pts. Monoclonal gammapathy was revealed in 11 (20,0%) of 55 cases. The amount of monoclonal immunoglobulin varied from 2.6 to 14.1 g/l. Monoclonal immunoglobulin Gk was detected in 5 of 11 pts, Gλ - in 2, Mλ - in 2, Mk - in 2. Monoclonal gammapathy was accompanied by polyclonal hypergammaglobulinaemia in 9 of 11 cases, hypogammaglobulinaemia - in 2. CONCLUSION: Quantitative and qualitative immunoglobulinopathies are observed in most patients at the onset of AITL. Quantitative abnormalities were determined more often than qualitative. Monoclonal gammapathy can be a manifestation of lymphoproliferation and other concomitant disorders. The prognostic value of immunochemical parameters is still unclear and requires dynamic observation and study.