Manish Butte

Prophylaxis of Upper Airway Infections in a Patient with Partial IgA Deficiency: Concurrent Use of Sublingual Immunotherapy with Inactivated Whole-Cell Bacterial Extract and Der p1.

September 11, 2020 By Manish Butte

Prophylaxis of Upper Airway Infections in a Patient with Partial IgA Deficiency: Concurrent Use of Sublingual Immunotherapy with Inactivated Whole-Cell Bacterial Extract and Der p1.

Case Rep Otolaryngol. 2020;2020:6313176

Authors: Aarestrup PF, Aarestrup MF, Aarestrup BJV, Aarestrup FM

Abstract
Selective IgA deficiency is the most common type of primary immunodeficiency, but there is not yet a specific effective treatment. The most prevalent clinical manifestations are infectious diseases of the respiratory system. We report herein the case of an 11-year-old female with selective IgA deficiency and recurring episodes of respiratory infections associated with rhinitis and asthma. We evaluated the efficacy of sublingual immunotherapy combined with inactivated whole-cell bacterial extract and Der p1-specific immunotherapy. After 18 months of clinical follow-up, we observed a significant reduction in the number of episodes of respiratory infections associated with control of atopic diseases. We also observed a 3-fold increase in serum IgA levels compared to treatment initiation. This case demonstrates the potential utility of the concurrent use of sublingual immunotherapy with inactivated whole-cell bacterial extract and Der p1 for successful control of allergy and infection in partial selective IgA deficiency.

PMID: 32908754 [PubMed]

The Natural History of X-Linked Lymphoproliferative Disease (XLP1): Lessons from a Long-Term Survivor.

September 11, 2020 By Manish Butte

The Natural History of X-Linked Lymphoproliferative Disease (XLP1): Lessons from a Long-Term Survivor.

Case Reports Immunol. 2020;2020:8841571

Authors: Jiang Y, Firan M, Nandiwada SL, Reyes A, Marsh RA, Vogel TP, Hajjar J

Abstract
X-linked lymphoproliferative disease (XLP1) is a rare primary immunodeficiency characterized by EBV-triggered immune dysregulation, lymphoproliferation, dysgammaglobulinemia, and lymphoma. Early childhood mortality from overwhelming inflammation is expected in most patients. The only curative therapy is hematopoietic stem cell transplant (HSCT); however, whether to perform HSCT on an asymptomatic patient remains debatable. This uncertainty arises because the natural history of XLP1 patients without transplantation is not clear. In this case report, we present the natural history of XLP1 in a 43-year-old male patient who did not receive HSCT. We also review the literature on untransplanted XLP1 patients who lived into mid-adulthood. Despite surviving childhood presentations that are typically fatal, we found that these rare patients remain susceptible to manifestations of XLP1 decades later.

PMID: 32908732 [PubMed]

[Treatment of deficiency of adenosine deaminase 2 caused by CECR1 mutation with myeloablative hematopoietic stem cell transplantation].

September 11, 2020 By Manish Butte

[Treatment of deficiency of adenosine deaminase 2 caused by CECR1 mutation with myeloablative hematopoietic stem cell transplantation].

Zhonghua Er Ke Za Zhi. 2020 Jun 02;58(6):509-511

Authors: Song XC, Zhou F

PMID: 32521966 [PubMed – indexed for MEDLINE]

Current Perspectives and Unmet Needs of Primary Immunodeficiency Care in Asia Pacific.

September 10, 2020 By Manish Butte

Current Perspectives and Unmet Needs of Primary Immunodeficiency Care in Asia Pacific.

Front Immunol. 2020;11:1605

Authors: Leung D, Chua GT, Mondragon AV, Zhong Y, Nguyen-Ngoc-Quynh L, Imai K, Vignesh P, Suratannon N, Mao H, Lee WI, Kim YJ, Chan GCF, Liew WK, Huong LTM, Kanegane H, Muktiarti D, Zhao X, Santos-Ocampo FJ, Latiff AHA, Seger R, Ochs HD, Singh S, Lee PP, Lau YL

Abstract
Background: The Asia Pacific Society for Immunodeficiencies (APSID) conducted nine primary immunodeficiency (PID) Schools in 5 years since inauguration to provide PID care training for early career physicians in Asia Pacific, a region with divergent needs in PID resources and training. Objective: To identify differences in PID patient care resource and training needs across Asia Pacific and propose a corresponding action plan. Methods: The Human Development Index (HDI) indicates the degree of socio-economic development in each country/region. Information related to investigations and learning issues were extracted from the abstracts and personal statements from all Schools and mapped onto resource and training needs. Correlations between HDI and country/region-specific parameters were tested by two-tailed Pearson correlation. Results: A total of 427 abstracts were received in nine Schools between 2015 and 2020, predominantly on immunodeficiencies affecting cellular and humoral immunity. Genetic confirmation was described in 61.8% of abstracts, and its absence negatively correlated with HDI (r = -0.696, p = 0.004). Essential immunologic and genetic tests were not available in 25.4 and 29.5% of abstracts, respectively, and their absence negatively correlated with HDI (r = -0.788, p < 0.001; r = -0.739, p = 0.002). HDI positively correlated with average testing level (r = 0.742, p = 0.002). Cases from medium-HDI countries/regions focused on learning how to investigate a patient for PIDs in cases of severe or atypical infections, whereas those from very-high-HDI countries/regions, from which most faculty members originated, listed hematopoietic stem cell transplantation and gene therapy, newborn screening, and research as learning issues more frequently. Conclusion: There are unique HDI-related PID resource and training needs in each country/region. APSID proposes HDI group-specific strategies to improve PID care and education in her member countries/regions. Further quantitative analysis of needs in PID care in Asia Pacific is needed for lobbying governments to increase their support for PID care and research.

PMID: 32903579 [PubMed – as supplied by publisher]

Intravenous Immunoglobulin G Suppresses Heat Shock Protein (HSP)-70 Expression and Enhances the Activity of HSP90 and Proteasome Inhibitors.

September 10, 2020 By Manish Butte

Intravenous Immunoglobulin G Suppresses Heat Shock Protein (HSP)-70 Expression and Enhances the Activity of HSP90 and Proteasome Inhibitors.

Front Immunol. 2020;11:1816

Authors: Jones RJ, Singh RK, Shirazi F, Wan J, Wang H, Wang X, Ha MJ, Baljevic M, Kuiatse I, Davis RE, Orlowski RZ

Abstract
Intravenous immunoglobulin G (IVIgG) is approved for primary immunodeficiency syndromes but may induce anti-cancer effects, and while this has been attributed to its anti-inflammatory properties, IgG against specific tumor targets may play a role. We evaluated IVIgG alone, and with a Heat shock protein (HSP)-90 or proteasome inhibitor, using multiple myeloma and mantle cell lymphoma (MCL) cells in vitro, and with the proteasome inhibitor bortezomib in vivo. IVIgG inhibited the growth of all cell lines tested, induced G1 cell cycle arrest, and suppressed pro-tumor cytokines including Interleukin (IL)-6, IL-8, and IL-10. Genomic and proteomic studies showed that IVIgG reduced tumor cell HSP70-1 levels by suppressing the ability of extracellular HSP70-1 to stimulate endogenous HSP70-1 promoter activity, and reduced extracellular vesicle uptake. Preparations of IVIgG were found to contain high titers of anti-HSP70-1 IgG, and recombinant HSP70-1 reduced the efficacy of IVIgG to suppress HSP70-1 levels. Combining IVIgG with the HSP90 inhibitor AUY922 produced superior cell growth inhibition and correlated with HSP70-1 suppression. Also, IVIgG with bortezomib or carfilzomib was superior to each single agent, and enhanced bortezomib’s activity in bortezomib-resistant myeloma cells. Moreover, IVIgG reduced transfer of extracellular vesicles (EVs) to cells, and blocked transfer of bortezomib resistance through EVs. Finally, IVIgG with bortezomib were superior to the single agents in an in vivo myeloma model. These studies support the possibility that anti-HSP70-1 IgG contained in IVIgG can inhibit myeloma and MCL growth by interfering with a novel mechanism involving uptake of exogenous HSP70-1 which then induces its own promoter.

PMID: 32903557 [PubMed – as supplied by publisher]

Impaired memory B-cell development and antibody maturation with a skewing toward IgE in patients with STAT3 hyper-IgE syndrome.

September 10, 2020 By Manish Butte

Impaired memory B-cell development and antibody maturation with a skewing toward IgE in patients with STAT3 hyper-IgE syndrome.

Allergy. 2019 12;74(12):2394-2405

Authors: van de Veen W, Krätz CE, McKenzie CI, Aui PM, Neumann J, van Noesel CJM, Wirz OF, Hagl B, Kröner C, Spielberger BD, Akdis CA, van Zelm MC, Akdis M, Renner ED

Abstract
BACKGROUND: Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is caused by heterozygous mutations in the STAT3 gene and is associated with eczema, elevated serum IgE, and recurrent infections resembling severe atopic dermatitis, while clinically relevant specific IgE is almost absent.
METHODS: To investigate the impact of STAT3 signaling on B-cell responses, we assessed lymph node and bone marrow, blood B and plasma cell subsets, somatic hypermutations in Ig genes, and in vitro proliferation and antibody production in STAT3-HIES patients and healthy controls.
RESULTS: Lymph nodes of STAT3-HIES patients showed normal germinal center architecture and CD138+ plasma cells residing in the paracortex, which expressed IgE, IgG, and IgM but not IgA. IgE+ plasma cells were abundantly present in STAT3-HIES bone marrow. Proliferation of naive B cells upon stimulation with CD40L and IL-4 was similar in patients and controls, while patient cells showed reduced responses to IL-21. IgE, IgG1, IgG3 and IgA1 transcripts showed reduced somatic hypermutations. Peripheral blood IgE+ memory B-cell frequencies were increased in STAT3-HIES, while other memory B-cell frequencies except for IgG4+ cells were decreased.
CONCLUSIONS: Despite impaired STAT3 signaling, STAT3-HIES patients can mount in vivo T-cell-dependent B-cell responses, while circulating memory B cells, except for those expressing IgG4 and IgE, were reduced. Reduced molecular maturation demonstrated the critical need of STAT3 signaling for optimal affinity maturation and B-cell differentiation, supporting the need for immunoglobulin substitution therapy and explaining the high IgE serum level in the majority with absent allergic symptoms.

PMID: 31269238 [PubMed – indexed for MEDLINE]

Hereditary angioedema cosegregating with a novel kininogen 1 gene mutation changing the N-terminal cleavage site of bradykinin.

September 10, 2020 By Manish Butte

Hereditary angioedema cosegregating with a novel kininogen 1 gene mutation changing the N-terminal cleavage site of bradykinin.

Allergy. 2019 12;74(12):2479-2481

Authors: Bork K, Wulff K, Rossmann H, Steinmüller-Magin L, Braenne I, Witzke G, Hardt J

PMID: 31087670 [PubMed – indexed for MEDLINE]

Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity.

September 10, 2020 By Manish Butte

Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity.

Sci Rep. 2019 02 22;9(1):2627

Authors: Yeo AJ, Henningham A, Fantino E, Galbraith S, Krause L, Wainwright CE, Sly PD, Lavin MF

Abstract
Respiratory disease is a major cause of morbidity and mortality in patients with ataxia-telangiectasia (A-T) who are prone to recurrent sinopulmonary infections, bronchiectasis, pulmonary fibrosis, and pulmonary failure. Upper airway infections are common in patients and S. pneumoniae is associated with these infections. We demonstrate here that the upper airway microbiome in patients with A-T is different from that to healthy controls, with S. pneumoniae detected largely in patients only. Patient-specific airway epithelial cells and differentiated air-liquid interface cultures derived from these were hypersensitive to infection which was at least in part due to oxidative damage since it was partially reversed by catalase. We also observed increased levels of the pro-inflammatory cytokines IL-8 and TNF-α (inflammasome-independent) and a decreased level of the inflammasome-dependent cytokine IL-β in patient cells. Further investigation revealed that the ASC-Caspase 1 signalling pathway was defective in A-T airway epithelial cells. These data suggest that the heightened susceptibility of these cells to S. pneumoniae infection is due to both increased oxidative damage and a defect in inflammasome activation, and has implications for lung disease in these patients.

PMID: 30796268 [PubMed – indexed for MEDLINE]

Targeting FcRn for immunomodulation: Benefits, risks, and practical considerations.

September 9, 2020 By Manish Butte

Targeting FcRn for immunomodulation: Benefits, risks, and practical considerations.

J Allergy Clin Immunol. 2020 Sep;146(3):479-491.e5

Authors: Peter HH, Ochs HD, Cunningham-Rundles C, Vinh DC, Kiessling P, Greve B, Jolles S

Abstract
The neonatal fragment crystallizable (Fc) receptor (FcRn) functions as a recycling mechanism to prevent degradation and extend the half-life of IgG and albumin in the circulation. Several FcRn inhibitors selectively targeting IgG recycling are now moving rapidly toward clinical practice in neurology and hematology. These molecules accelerate the destruction of IgG, reducing pathogenic IgG and IgG immune complexes, with no anticipated effects on IgA, IgM, IgE, complement, plasma cells, B cells, or other cells of the innate or adaptive immune systems. FcRn inhibitors have potential for future use in a much wider variety of antibody-mediated autoimmune diseases. Given the imminent clinical use, potential for broader utility, and novel mechanism of action of FcRn inhibitors, here we review data from 4 main sources: (a) currently available activity, safety, and mechanism-of-action data from clinical trials of FcRn inhibitors; (b) other procedures and treatments that also remove IgG (plasma donation, plasma exchange, immunoadsorption); (c) diseases resulting in loss of IgG; and (d) primary immunodeficiencies with potential mechanistic similarities to those induced by FcRn inhibitors. These data have been evaluated to provide practical considerations for the assessment, monitoring, and reduction of any potential infection risk associated with FcRn inhibition, in addition to highlighting areas for future research.

PMID: 32896308 [PubMed – in process]

[Hereditary angioedema in Costa Rica].

September 8, 2020 By Manish Butte

[Hereditary angioedema in Costa Rica].

Rev Alerg Mex. 2020 Apr-Jun;67(2):102-111

Authors: Alfaro-Murillo AJ, Martínez-Alfonso M, Castro-Cordero J, León-Bratti MP, Ivankovich-Escoto G, Espinoza-Mora MR

Abstract
BACKGROUND: Hereditary angioedema is classified as a primary immunodeficiency of the complement system because it is characterized by the absence of C1 esterase inhibitor (C1-INH) and by the periodic edema of any region of the body that involves soft tissue.
OBJECTIVE: To characterize the adult patients with a confirmed diagnosis of hereditary angioedema who have been treated in the Clinical Allergology Department of Hospital México de la Caja Costarricense del Seguro Social.
METHODS: The study was retrospective and observational. The information was obtained from the clinical records of the patients with a confirmed diagnosis of hereditary angioedema that were being controlled in the Allergology Department of the “Hospital México de la Caja Costarricense del Seguro Social”.
RESULTS: A total of 14 patients; seven men and seven women, were identified. The average was of 36.6 years of age. The most frequent clinical manifestations were peripheral edema and abdominal pain. Only three patients presented laryngeal edema at some point in their evolution. 12 cases corresponded to hereditary angioedema type I.
CONCLUSION: The clinical characteristics of all the documented cases corresponded to those described for this pathology, although only a few patients had a history of severe manifestations.

PMID: 32892525 [PubMed – in process]