Manish Butte

Autoimmunity and Inflammation in CVID: a Possible Crosstalk between Immune Activation, Gut Microbiota, and Epigenetic Modifications.

J Clin Immunol. 2018 Nov 21;:

Authors: Jørgensen SF, Fevang B, Aukrust P

Abstract
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency among adults and is characterized by a B cell dysfunction and increased risk of respiratory tract infections with encapsulated bacteria. However, a large proportion of patients also has inflammatory and autoimmune complications. It may seem like a paradox that immunodeficiency and inflammation/autoimmunity coexist within the same individuals. In this commentary, we propose that CVID immunopathogenesis involves an interplay of genes, environmental factors, and dysregulation of immune cells, where gut microbiota and gastrointestinal inflammation can both be important contributors or endpoints to the systemic immune activation seen in CVID, and where epigenetic mechanism may be the undiscovered link between these contributors. In our opinion, these pathways could represent novel targets for therapy in CVID directed against autoimmune and inflammatory manifestations that represent the most severe complications in these patients. Considering the heterogeneous nature of CVID, these mechanisms may not be present in all patients, and different complications may be triggered by different risk factors. CVID is really a variable disease and in the future there is clearly a need for a more personalized medicine based on both genotypic and phenotypic findings.

PMID: 30465180 [PubMed – as supplied by publisher]

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Treatment Satisfaction with Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary Immunodeficiency: a Pooled Analysis of Six Hizentra® Studies.

J Clin Immunol. 2018 Nov 21;:

Authors: Mallick R, Jolles S, Kanegane H, Agbor-Tarh D, Rojavin M

Abstract
PURPOSE: Primary immunodeficiency diseases (PIDDs) are a heterogenous group of disorders characterized by intrinsic impairment in the immune system. Most patients with PIDD require life-long immunoglobulin G replacement therapy, which has been shown to reduce the rate of infections and, related hospitalizations and reduce health-related quality of life (HRQOL). Here, treatment satisfaction and HRQOL in patients with PIDD was evaluated upon switching from intravenous (IVIG) or subcutaneous immunoglobulins (SCIGs) to 20% SCIG (Hizentra®), and during long-term steady-state Hizentra® treatment.
METHODS: Analyses were based on two pivotal (switch) and four extension/follow-up (maintenance) Phase III studies of Hizentra® conducted in Europe (EU), Japan (JP), and the United States (US). Two validated questionnaires were used: Life Quality Index (LQI) for assessment of IgG-specific perceptions of HRQOL and Short Form 36 version 2 (SF-36v2).
RESULTS: In the EU and JP switch studies, there was significant and meaningful improvement from Screening in LQI domain scores at all time points, largely driven by patients switching from IVIG to SCIG. In the EU switch study, there were also significant increases in mean SF-36v2 domain scores for Physical Function and General Health from Screening to Week 12. These improvements were observed also at Week 24. Overall, LQI and SF-36v2 domain scores were generally sustained in the maintenance studies.
CONCLUSIONS: These results showed that switching patients from IVIG to SCIG improves patient self-reported health status and IgG-specific HRQOL perception. The maintenance studies generally showed no deterioration of this improved health status over a long follow-up period.

PMID: 30465179 [PubMed – as supplied by publisher]

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Bronchial Asthma and Bronchial Hyperresponsiveness and Their Characteristics in Patients with Common Variable Immunodeficiency.

Int Arch Allergy Immunol. 2018 Nov 20;:1-9

Authors: Milota T, Bloomfield M, Parackova Z, Sediva A, Bartunkova J, Horvath R

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) is one of the most frequent primary immunodeficiencies and is characterized by disturbed immunoglobulin production and dysregulation of the immune system. Results of previous studies suggest a higher prevalence of bronchial asthma (BA) in CVID patients than in the general population. We initiated this study to evaluate lung functions and identify risk factors for BA and bronchial hyperresponsiveness (BHR) in patients with CVID.
METHODS: Twenty-three patients with CVID were included in this study. In all of them, spirometry and a metacholine bronchoprovocation test were performed. We also investigated the role of atopy, eosinophilic inflammation, and potential risk factors such as gender, age, or immunoglobulin levels at the time of diagnosis.
RESULTS: BHR was confirmed in 12 patients (52%), all of whom had normal FEV1 and FEV1/FVC. However, BHR-positive patients had significantly decreased MEF25. BHR-positive patients had also more symptoms related to bronchial obstruction, with 8 of them (35%) being suspected of having BA at the end of the study. A higher prevalence of BHR was found in females, with a relative risk of 2.89.
CONCLUSIONS: An increased prevalence of BHR and BA was detected in CVID patients compared to the general population. BA may develop despite the disturbed immunoglobulin production, and the majority of patients display nonatopic and noneosinophilic properties. These results suggest a limited role of atopy and eosinophilic inflammation in the pathogenesis of BA in CVID patients.

PMID: 30458444 [PubMed – as supplied by publisher]

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[Chronic granulomatous disease: multiple infections as clinical presentation. Pediatric case report].

Arch Argent Pediatr. 2018 Dec 01;116(6):e744-e748

Authors: Maydana M, Cabanillas D, Regairaz L, Bastons S, Uriarte V, García M, Sosa MF, Vinuesa M, Del Palacio P, Morales J

Abstract
Chronic granulomatous disease is an uncommon primary immunodeficiency due to a defect of the killing activity of phagocytes, caused by mutations in any of the genes encoding subunits of the superoxide-generating phagocyte NADPH oxidase system. The incidence is 1 in 250 000 live births. It can occur from infancy to adulthood, usually in children under 2 years. Bacterial and fungal infections in association with granuloma lesions are the most common manifestations of the disease. Aspergillus species, Staphylococcus aureus, Serratia marcescens, Nocardia species are the most common microorganisms isolated. We describe here a case of a 1-year-old boy with chronic granulomatous disease and invasive pulmonary aspergillosis, Serratia marcescens osteomyelitis and Enterobacter cloacae cervical granuloma.

PMID: 30457728 [PubMed – in process]

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Gastric Cancer Is the Leading Cause of Death in Italian Adult Patients With Common Variable Immunodeficiency.

Front Immunol. 2018;9:2546

Authors: Pulvirenti F, Pecoraro A, Cinetto F, Milito C, Valente M, Santangeli E, Crescenzi L, Rizzo F, Tabolli S, Spadaro G, Agostini C, Quinti I

Abstract
An increased prevalence of malignant lymphoma and of gastric cancer has been observed in large cohorts of patients with common variable immunodeficiency (CVID), the most frequently symptomatic primary immunodeficiency. Surveillance strategies for cancers in CVID should be defined based on epidemiological data. Risks and mortality for cancers among 455 Italian patients with CVID were compared to cancer incidence data from the Italian Cancer Registry database. CVID patients showed an increased cancer incidence for all sites combined (Obs = 133, SIR = 2.4; 95%CI = 1.7-3.5), due to an excess of non-Hodgkin lymphoma (Obs = 33, SIR = 14.3; 95%CI = 8.4-22.6) and of gastric cancer (Obs = 25; SIR = 6.4; 95%CI = 3.2-12.5). CVID patients with gastric cancer and lymphoma had a worse survival in comparison to cancer-free CVID (HR: 4.8, 95%CI: 4.2-44.4 and HR: 4.2, 95%CI: 2.8-44.4). Similar to what observed in other series, CVID-associated lymphomas were more likely to be of B cell origin and often occurred at extra-nodal sites. We collected the largest case-series of gastric cancers in CVID subjects. In contrast to other reports, gastric cancer was the leading cause of death in CVID. Standardized mortality ratio indicated a 10.1-fold excess mortality among CVID patients with gastric cancer. CVID developed gastric cancer 15 years earlier than the normative population, but they had a similar overall survival. Only CVID diagnosed at early stage gastric cancer survived >24 months. Stomach histology from upper endoscopy performed before cancer onset showed areas of atrophic gastritis, intestinal metaplasia or dysplasia. CVID patients might progress rapidly to an advanced cancer stage as shown by patients developing a III-IV stage gastric cancer within 1 year from an endoscopy without signs of dysplasia. Based on high rate of mortality due to gastric cancer in Italian CVID patients, we hereby suggest a strategy aimed at early diagnosis, based on regular upper endoscopy and on Helicobacter pylori infection treatment, recommending an implementation of national guidelines.

PMID: 30455695 [PubMed – in process]

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Genomic loci associated with antibody-mediated immune responses in an F2 chicken population.

Animal. 2018 Nov 19;:1-9

Authors: Raeesi V, Ehsani A, Torshizi RV

Abstract
Immunity-related traits are heritable in chicken, therefore, it is possible to improve the inherent immunity by breeding programs. In this study using the Illumina chicken 60K single nucleotide polymorphisms (SNPs) chip, we performed a set of genome-wide association studies to determine candidate genes and loci responsible for primary and secondary antibody-mediated responses against sheep red blood cell. A F2 population descended from a commercial meat-type breed and an Iranian indigenous chicken was used for this study. Statistical analysis was based on a mixed linear model utilizing genomic relationship matrix to prevent spurious associations. Correction for multiple testing was done by applying 5% and 10% chromosomal false discovery rates (FDRs) for significant and suggestive thresholds, respectively. Nine significant and 17 suggestive associated SNPs were identified. Most of the SNPs that were suggestively associated with the primary response of total plasma immunoglobulins were also significantly associated with this trait in secondary response. Three SNPs were located within a narrow region of 23 kb on chromosome 16. Pathway analysis for the genes surrounding the associated SNPs showed that they are involve in antigen processing and presentation, primary immunodeficiency, vitamin digestion and absorption, cell adhesion molecules, phagosome, influenza A, folding, assembly and peptide loading of class I major histocompatibility complex, lipid digestion, mobilization, and transport (FDR < 0.1). Interestingly, there were common regains associated with multiple immune-related traits.

PMID: 30451125 [PubMed – as supplied by publisher]

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The Phenotype and Treatment of WIP Deficiency: Literature Synopsis and Review of a Patient With Pre-transplant Serial Donor Lymphocyte Infusions to Eliminate CMV.

Front Immunol. 2018;9:2554

Authors: Schwinger W, Urban C, Ulreich R, Sperl D, Karastaneva A, Strenger V, Lackner H, Boztug K, Albert MH, Benesch M, Seidel MG

Abstract
Early diagnosis of primary immunodeficiency disorders (PID) is vital and allows directed treatment, especially in syndromes with severe or profound combined immunodeficiency. In PID patients with perinatal CMV or other opportunistic, invasive infections (e.g., Pneumocystis or Aspergillus), multi-organ morbidity may already arise within the first months of life, before hematopoietic stem cell transplantation (HSCT) or gene therapy can be undertaken, compromising the definitive treatment and outcome. Deficiency of Wiskott-Aldrich syndrome (WAS) protein-interacting protein (WIP deficiency) causes an autosomal recessive, WAS-like syndrome with early-onset combined immunodeficiency that has been described in three pedigrees to date. While WAS typically includes combined immunodeficiency, microthrombocytopenia, and eczema, the clinical and laboratory phenotypes of WIP-deficient patients-including lymphocyte subsets, platelets, lymphocyte proliferation in vitro, and IgE-varied widely and did not entirely recapitulate WAS, impeding early diagnosis in the reported patients. To elucidate the phenotype of WIP deficiency, we provide a comprehensive synopsis of clinical and laboratory features of all hitherto-described patients (n = 6) and WIP negative mice. Furthermore, we summarize the treatment modalities and outcomes of these patients and review in detail the course of one of them who was successfully treated with serial, unconditioned, maternal, HLA-identical donor lymphocyte infusions (DLI) against life-threatening, invasive CMV infection, followed by a TCRαβ/CD19-depleted, treosulfan/melphalan-conditioned, peripheral blood HSCT and repetitive, secondary-prophylactic, CMV-specific DLI with 1-year post-HSCT follow-up. This strategy could be useful in other patients with substantial premorbidity, considered “too bad to transplant,” who have an HLA-identical family donor, to eliminate infections and bridge until definitive treatment.

PMID: 30450104 [PubMed – in process]

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Clinicopathological analysis of primary intestinal diffuse large B-cell lymphoma: Prognostic evaluation of CD5, PD-L1, and Epstein-Barr virus on tumor cells.

Cancer Med. 2018 Nov 18;:

Authors: Ishikawa E, Kato S, Shimada K, Tanaka T, Suzuki Y, Satou A, Kohno K, Sakakibara A, Yamamura T, Nakamura M, Miyahara R, Goto H, Nakamura S, Hirooka Y

Abstract
BACKGROUND: Primary intestinal diffuse large B-cell lymphoma (iDLBCL) is rare. In this study, we investigated the clinicopathological features of this disease to further understand the prognostic value of CD5, programmed cell death ligand 1 (PD-L1), and Epstein-Barr virus (EBV) on tumor cells.
METHODS: Tumor specimens from 62 patients consecutively diagnosed with primary iDLBCL at a single institution were analyzed.
RESULTS: Our series consisted of EBV-positive (EBV+ ) iDLBCL (n = 10), de novo CD5+ iDLBCL (n = 4), and DLBCL, not otherwise specified (DLBCL-NOS; n = 48). Notably, seven of 10 EBV+ cases had treated lymphoma-associated (n = 4) or iatrogenic immunodeficiency (n = 3). Two of 10 EBV+ cases expressed PD-L1 on tumor cells, whereas the remaining eight were positive for PD-L1 on microenvironment immune cells. Only one DLBCL-NOS case had neoplastic PD-L1 expression with a giant cell-rich appearance. Both EBV-harboring and PD-L1 expression on tumor cells, but not CD5, were associated with worse overall survival (OS) in iDLBCL patients receiving rituximab-containing chemotherapy (P = 0.0354, P = 0.0092, and P = 0.1097, respectively). Multivariate analysis identified PD-L1 positivity on tumor cells (P = 0.0106), PD-L1 negativity on microenvironment immune cells (P = 0.0193), and EBV positivity (P = 0.0324) as poor independent prognostic factors for OS. Among iDLBCL cases without any EBV association, CD5 positivity, or neoplastic PD-L1 expression, high PD-L1 expression (≥40%) on microenvironment immune cells predicted an extremely favorable outcome.
CONCLUSION: EBV+ iDLBCL mainly comprised immunodeficiency-associated patients, which may highlight the specificity of the intestine. PD-L1 expression on tumor cells or microenvironment immune cells was found to have an opposite prognostic impact in iDLBCL.

PMID: 30449068 [PubMed – as supplied by publisher]

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