Manish Butte

Integrin Binding to the Trimeric Interface of CD40L Plays a Critical Role in CD40/CD40L Signaling.

April 9, 2020 By Manish Butte

Integrin Binding to the Trimeric Interface of CD40L Plays a Critical Role in CD40/CD40L Signaling.

J Immunol. 2019 09 01;203(5):1383-1391

Authors: Takada YK, Yu J, Shimoda M, Takada Y

Abstract
CD40L plays a major role in immune response and is a major therapeutic target for inflammation. Integrin α5β1 and CD40 simultaneously bind to CD40L. It is unclear if α5β1 and CD40 work together in CD40/CD40L signaling or how α5β1 binds to CD40L. In this article, we describe that the integrin-binding site of human CD40L is predicted to be located in the trimeric interface by docking simulation. Mutations in the predicted integrin-binding site markedly reduced the binding of α5β1 to CD40L. Several CD40L mutants defective in integrin binding were defective in NF-κB activation and B cell activation and suppressed CD40L signaling induced by wild-type CD40L; however, they still bound to CD40. These findings suggest that integrin α5β1 binds to monomeric CD40L through the binding site in the trimeric interface of CD40L, and this plays a critical role in CD40/CD40L signaling. Integrin αvβ3, a widely distributed vascular integrin, bound to CD40L in a KGD-independent manner, suggesting that αvβ3 is a new CD40L receptor. Several missense mutations in CD40L that induce immunodeficiency with hyper-IgM syndrome type 1 (HIGM1) are clustered in the integrin-binding site of the trimeric interface. These HIGM1 CD40L mutants were defective in binding to α5β1 and αvβ3 (but not to CD40), suggesting that the defect in integrin binding may be a causal factor of HIGM1. These findings suggest that α5β1 and αvβ3 bind to the overlapping binding site in the trimeric interface of monomeric CD40L and generate integrin-CD40L-CD40 ternary complex. CD40L mutants defective in integrins have potential as antagonists of CD40/CD40L signaling.

PMID: 31331973 [PubMed – indexed for MEDLINE]

Acquired Immunodeficiency from Maternal Chemotherapy and Severe Primary Pneumocystis Infection in an Infant.

April 8, 2020 By Manish Butte

Acquired Immunodeficiency from Maternal Chemotherapy and Severe Primary Pneumocystis Infection in an Infant.

Case Rep Pediatr. 2020;2020:5740304

Authors: Lim AYL, Mattke AC, Clark JE, Pinzon-Charry A, Alphonso N, Kapur N

Abstract
Pneumocystis jirovecii is recognized as an opportunistic pathogen in immunosuppressed patients. We report a case of severe Pneumocystis pneumonia (PCP) in an infant with acquired combined immunodeficiency secondary to maternal chemotherapy exposure during the second and third trimesters of pregnancy. The infant required cardiorespiratory support with veno-venous extracorporeal membrane oxygenation (VV-ECMO) for severe respiratory failure. This case highlights the potential for severe acquired immunodeficiency in this patient cohort and further postnatal surveillance is highly recommended.

PMID: 32257491 [PubMed – as supplied by publisher]

Newborn Screening for Presymptomatic Diagnosis of Complement and Phagocyte Deficiencies.

April 8, 2020 By Manish Butte

Newborn Screening for Presymptomatic Diagnosis of Complement and Phagocyte Deficiencies.

Front Immunol. 2020;11:455

Authors: Dezfouli M, Bergström S, Skattum L, Abolhassani H, Neiman M, Torabi-Rahvar M, Franco Jarava C, Martin-Nalda A, Ferrer Balaguer JM, Slade CA, Roos A, Fernandez Pereira LM, López-Trascasa M, Gonzalez-Granado LI, Allende-Martinez LM, Mizuno Y, Yoshida Y, Friman V, Lundgren Å, Aghamohammadi A, Rezaei N, Hernández-Gonzalez M, von Döbeln U, Truedsson L, Hara T, Nonoyama S, Schwenk JM, Nilsson P, Hammarström L

Abstract
The clinical outcomes of primary immunodeficiencies (PIDs) are greatly improved by accurate diagnosis early in life. However, it is not common to consider PIDs before the manifestation of severe clinical symptoms. Including PIDs in the nation-wide newborn screening programs will potentially improve survival and provide better disease management and preventive care in PID patients. This calls for the detection of disease biomarkers in blood and the use of dried blood spot samples, which is a part of routine newborn screening programs worldwide. Here, we developed a newborn screening method based on multiplex protein profiling for parallel diagnosis of 22 innate immunodeficiencies affecting the complement system and respiratory burst function in phagocytosis. The proposed method uses a small fraction of eluted blood from dried blood spots and is applicable for population-scale performance. The diagnosis method is validated through a retrospective screening of immunodeficient patient samples. This diagnostic approach can pave the way for an earlier, more comprehensive and accurate diagnosis of complement and phagocytic disorders, which ultimately lead to a healthy and active life for the PID patients.

PMID: 32256498 [PubMed – as supplied by publisher]

Evidence-based telehealth clinical pathway for pediatric tympanostomy tube otorrhea.

April 7, 2020 By Manish Butte

Evidence-based telehealth clinical pathway for pediatric tympanostomy tube otorrhea.

Int J Pediatr Otorhinolaryngol. 2020 Mar 27;134:110027

Authors: Shaffer AD, Dohar JE

Abstract
INTRODUCTION: As healthcare moves away from volume-based to value-based delivery models, evidence based clinical pathways detail essential steps in patient care to reduce the costs and utilization of health care resources. Ideal pathways lead towards standardized, patient-centered care through an algorithm that is evidence-based, interventions with criteria-based progression, and measurable endpoints or quality indicators. Using these standards, a clinical pathway for managing tympanostomy tube otorrhea beginning with phone triage was developed in accordance with AAO-HNSF Guidelines.
METHODS: A retrospective case series of all consecutive patients calling the otolaryngology nurse’s line at a tertiary pediatric hospital 3/2018-11/2018 regarding otorrhea was performed. Nurses completed a standardized and evidence-based form based on parent responses regarding purulence, tympanostomy tubes/perforation, fever>102°, ear redness, bacterial rhinosinusitis, sore throat, and immunodeficiency, which was sent to the advanced practice providers (APPs) to assess for antibiotic drops. Otorrhea form information and tympanostomy tube history, subsequent phone calls, clinic visits, and antibiotic prescriptions for otorrhea were extracted.
RESULTS: Eighty-two patients were included. Median child age at phone call was 2.5 years (range 0.3-20.2 years), and 45.1% were female. All patients had prior tubes and active purulent otorrhea. No parents reported cellulitis or immunodeficiency. One patient had symptoms of bacterial rhinosinusitis and a sore throat but had already been seen by their primary care provider (PCP) for systemic antibiotics. Antibiotic drops were prescribed by an APP in 96.3% of cases [ofloxacin (n = 57), ciprofloxacin (n = 17), or ciprofloxacin with dexamethasone (n = 5)]. The remaining patients already had drops (2.5%) or were referred to their PCP (1.2%). Twenty (24.4%) received another antibiotic prescription and 17.1% had a subsequent clinic or urgent care visit for otorrhea.
CONCLUSIONS: This pathway obviated clinic visits in 82.9% of patients with a 75.6% treatment cure.

PMID: 32251973 [PubMed – as supplied by publisher]

Interleukin-6 use in COVID-19 pneumonia related macrophage activation syndrome.

April 7, 2020 By Manish Butte

Interleukin-6 use in COVID-19 pneumonia related macrophage activation syndrome.

Autoimmun Rev. 2020 Apr 03;:102537

Authors: McGonagle D, Sharif K, O’Regan A, Bridgewood C

Abstract
Severe COVID-19 associated pneumonia patients may exhibit features of systemic hyper-inflammation designated under the umbrella term of macrophage activation syndrome (MAS) or cytokine storm, also known as secondary haemophagocytic lymphohistocytosis (sHLH). This is distinct from HLH associated with immunodeficiency states termed primary HLH -with radically different therapy strategies in both situations. COVID-19 infection with MAS typically occurs in subjects with adult respiratory distress syndrome (ARDS) and historically, non-survival in ARDS was linked to sustained IL-6 and IL-1 elevation. We provide a model for the classification of MAS to stratify the MAS-like presentation in COVID-19 pneumonia and explore the complexities of discerning ARDS from MAS. We describe the potential impact of viral load and therapy timing towards improving the outcome of IL-6 antagonism and other immunomodulatory therapies.

PMID: 32251717 [PubMed – as supplied by publisher]

Autosomal Dominant Hyper IgE Syndrome from a single center in Chongqing, China (2009-2018).

April 6, 2020 By Manish Butte

Autosomal Dominant Hyper IgE Syndrome from a single center in Chongqing, China (2009-2018).

Scand J Immunol. 2020 Apr 05;:e12885

Authors: Xiang Q, Zhang L, Liu X, Wang S, Wang T, Xiao M, Zhao X, Jiang L

Abstract
Autosomal dominant hyper IgE syndrome (AD-HIES) caused by STAT3 gene mutation is a rare primary immunodeficiency disease. To better understand the disease, we described the clinical characteristics of 20 AD-HIES patients in Chongqing, China and explored the effect of mutations in different domains of STAT3 gene on the function of STAT3 protein by western blot and confocal microscopy. The mean age at onset was 0.12 years. The mean age at diagnosis was 5.31 years. The most common presentation was eczema, pneumonia, skin abscesses and chronic mucocutaneous candidiasis. Seven patients suffered from BCG complications. R382W/Q were identified in 12 patients, V637M mutation in 3 patients. Three patients have died. The phosphorylated STAT3 was expressed more in wild-type(WT) and R382W mutant STAT3 in the cytoplasm of COS7 cells with epidermal growth factor(EGF) stimulation, less in the V637M mutation and T620S mutation. Dynamic observation showed that STAT3 cytoplasmic accumulation and nuclear translocation occurred rapidly after EGF stimulation in WT-STAT3-GFP, the time of accumulation and nuclear translocation was later and the expression was less in R382W-STAT3-GFP compared with WT-STAT3-GFP, followed by V637M and T620S mutation. These results suggested that our patients had earlier onset, diagnostic age and higher rate of BCG complications. However, our patients had higher incidence of mortality though the earlier diagnostic age. We did not find a significant genotype/phenotype correlation, but Src homology 2 domain mutations (V637M and T620S) had a greater effect on STAT3 phosphorylation and nuclear translocation than DNA-binding domain mutation (R382W) in vitro.

PMID: 32248557 [PubMed – as supplied by publisher]

Interstitial lung disease in primary immunodeficiency: towards a brighter future.

April 5, 2020 By Manish Butte

Interstitial lung disease in primary immunodeficiency: towards a brighter future.

Eur Respir J. 2020 Apr;55(4):

Authors: Hurst JR, Warnatz K, ERS eGLILDnet Clinical Research Collaboration

PMID: 32245772 [PubMed – as supplied by publisher]

Chediak-Higashi syndrome: Lessons from a single-centre case series.

April 4, 2020 By Manish Butte

Chediak-Higashi syndrome: Lessons from a single-centre case series.

Allergol Immunopathol (Madr). 2019 Nov – Dec;47(6):598-603

Authors: Carneiro IM, Rodrigues A, Pinho L, de Jesus Nunes-Santos C, de Barros Dorna M, Moschione Castro APB, Pastorino AC

Abstract
BACKGROUND: Chediak-Higashi syndrome (CHS) is a rare and potentially fatal autosomal recessive disease characterized by frequent bacterial infections, bleeding tendency, oculocutaneous albinism, photosensitivity and progressive neurologic dysfunction. Owing to the rarity of this condition, the objective of this study was to describe patients with CHS.
METHODS: Retrospective evaluation of patients followed in a paediatric tertiary centre of Allergy and Immunology of São Paulo, Brazil, between 1986 and 2018 with a confirmed diagnosis of CHS. Data were obtained from medical records. Demographic aspects, family history, clinical findings, laboratory data, diagnosis, treatment and outcome were described.
RESULTS: A total of 14 patients (five male) were included. Clinical manifestations were first recognized at a median age of two months (at birth-20 months). Median age at diagnosis was 1.7 years (0-5 years). All patients had recurrent infections. Albinism was present in 13 patients and silvery or light hair was present in 14. Seven patients developed hemophagocytic lymphohistiocytosis (HLH); the median age at the diagnosis of HLH was 5.7 years (2.6-6.7 years) and the median interval between the diagnosis of CHS and HLH was 3.3 years (0-5 years). Four of the most recently diagnosed patients underwent bone marrow transplantation (BMT). Nine patients are deceased, and one was lost to follow-up. The median age of death was 6.7 years (3.8-22 years). Five patients died of HLH, one of lymphoma, and three of infection. All the patients who had HLH before the year of 2000 died of HLH. The two most recently diagnosed patients with HLH were able to cure the HLH, although they died of other causes. Four patients are alive, three of them after successful BMT.
CONCLUSION: Thirty years of follow up showed an improvement in the prognosis in patients with CHS. The better understanding of the underlying biological mechanisms of HLH allowed the standardization of management protocols, resulting in survival improvement. BMT is the only treatment that can change CHS prognosis, which emphasizes the need for early identification of the disease.

PMID: 31477396 [PubMed – indexed for MEDLINE]

Protein spectrum changes in exosomes after therapeutic plasma exchange in patients with neuromyelitis optica.

April 3, 2020 By Manish Butte

Protein spectrum changes in exosomes after therapeutic plasma exchange in patients with neuromyelitis optica.

J Clin Apher. 2020 Apr 02;:

Authors: Ma C, Wang S, Wang G, Wu Y, Yang T, Shen W, Zhuang Y, Zhang L, Liu X, Yang L, Feng Y, Yu Y, Liu Z, Wang D

Abstract
INTRODUCTION: Neuromyelitis optica (NMO) is an autoimmune disease with a high rate of blindness and positive for the detection of aquaporin-4 antibody (AQP4) in most patients. NMO acute attacks are managed by high-doses of intravenous methylprednisolone followed by oral taper, and if symptoms fail to resolve, therapeutic plasma exchange (TPE) is added. TPE can remove pathological antibodies and inflammatory factors leading to clinical improvement.
METHODS: A total of 40 TPE fluid collections from the first to fifth TPE treatments were obtained from eight patients. Exosomes were isolated by ultracentrifugation. Mass spectrometry analyses were used to compare protein change in TPE fluid collection exosomes after the first to the fifth TPE treatments in these patients.
RESULTS: We detected 647 exosome proteins through data-independent acquisition analysis. It was found that some unknown functional antibody fragments and complement pathway proteins decreased after TPE treatment. The results revealed a significant involvement of the following two key pathways: the primary immunodeficiency and systemic lupus erythematosus that may be associated with NMO pathophysiology and TPE treatment efficacy (P < .05). A series of complement proteins may contribute to NMO; in addition, the following proteins increased with plasma exchange: complement factor H-related protein 5, bridging integrator 2, neuroplastin, pigment epithelium-derived factor, ficolin-1, extracellular matrix protein 1, and fatty acid-binding protein 5.
CONCLUSION: Our study may provide a new perspective on the pathogenesis and treatment efficacy of NMO.

PMID: 32240559 [PubMed – as supplied by publisher]

Immunological and Clinical Phenotyping in Primary Antibody Deficiencies: a Growing Disease Spectrum.

April 3, 2020 By Manish Butte

Immunological and Clinical Phenotyping in Primary Antibody Deficiencies: a Growing Disease Spectrum.

J Clin Immunol. 2020 Apr 02;:

Authors: Shin JJ, Liauw D, Siddiqui S, Lee J, Chung EJ, Steele R, Hsu FI, Price C, Kang I

Abstract
PURPOSE: Although common variable immunodeficiency (CVID) is considered the most prevalent symptomatic primary antibody deficiency (PAD), there is a population with symptomatic PADs that do not meet criteria for CVID. We analyzed clinical and immunological profiles of patients with different PADs to better understand the differences and similarities between CVID and other PADs.
METHODS: We extracted clinical and laboratory data of patients with PADs from electronic medical records. Patients were categorized into CVID, IgG subclass 2 deficiency (IgG2D), IgG deficiency (IgGD), and specific antibody deficiency (sAbD) based on basal immunoglobulin levels and pneumococcal vaccine responses. We compared clinical and immunological characteristics in these groups.
RESULTS: All patients, regardless of PAD types, showed similar frequencies of infections, bronchiectasis, and interstitial lung disease (ILD). Hematopoietic malignancies were more frequently found in the CVID than in the IgG2D, IgGD, and sAbD groups, while the latter groups trended towards an increased frequency of connective tissue diseases (CTD). Low counts of natural killer (NK) cells were associated with malignancy, autoimmunity, and ILD in CVID but not in other PAD groups.
CONCLUSIONS: Higher frequency of hematopoietic malignancy in CVID than in the other PADs and association of lower NK cell counts with non-infectious complications in CVID suggest a relationship between immune alterations and the development of non-infectious manifestations in PADs.

PMID: 32239366 [PubMed – as supplied by publisher]