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Genetics of Pediatric Immune-Mediated Diseases and Human Immunity.

February 4, 2021 By Manish Butte

Genetics of Pediatric Immune-Mediated Diseases and Human Immunity.

Annu Rev Immunol. 2021 Feb 03;:

Authors: Schmitt EG, Cooper MA

Abstract
Primary immunodeficiency diseases (PIDs) are a rapidly growing, heterogeneous group of genetically determined diseases characterized by defects in the immune system. While individually rare, collectively PIDs affect between 1/1,000 and 1/5,000 people worldwide. The clinical manifestations of PIDs vary from susceptibility to infections to autoimmunity and bone marrow failure. Our understanding of the human immune response has advanced by investigation and discovery of genetic mechanisms of PIDs. Studying patients with isolated genetic variants in proteins that participate in complex signaling pathways has led to an enhanced understanding of host response to infection, and mechanisms of autoimmunity and autoinflammation. Identifying genetic mechanisms of PIDs not only furthers immunological knowledge but also benefits patients by dictating targeted therapies or hematopoietic stem cell transplantation. Here, we highlight several of these areas in the field of primary immunodeficiency, with a focus on the most recent advances. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID: 33534603 [PubMed – as supplied by publisher]

Role of self-care in COVID-19 pandemic for people living with comorbidities of diabetes and hypertension.

February 4, 2021 By Manish Butte

Role of self-care in COVID-19 pandemic for people living with comorbidities of diabetes and hypertension.

J Family Med Prim Care. 2020 Nov;9(11):5495-5501

Authors: Gupta SK, Lakshmi PVM, Kaur M, Rastogi A

Abstract
People living with comorbidities especially chronic non-communicable disease (NCDs) like diabetes and hypertension are at greater risk of acquiring severe form of Corona Virus Disease (COVID-19) infection known to be caused by Severe Acute Respiratory Syndrome-CoV -2 (SARS-CoV-2) due to underlying immunodeficiency. The government has taken various public health measures to reduce the risk of infection, such as physical distancing, Information Education and Communication (IEC) messages regarding hand-washing, usage of masks, and avoidance of unnecessary travel including lockdown to combat the spread of disease. However, nationwide lockdown due to COVID-19 pandemic has also confronted the existing health care system (clinician centric approach) for the management of diabetes and hypertension in India. Using secondary source of data from specific website and search engine a review was done for existing guidelines and literature focusing on the various components of self-care management (patient-centered care) and highlights the importance of self-care management education to cope up with twin pandemic of COVID-19 and NCDs. An attempt was also made to highlight the use of eHealth to manage diabetes and hypertension which may act as a bridge to fill the gap between primary care physician and patient’s amid lockdown and help physician to deliver comprehensive care for people suffering from comorbidities.

PMID: 33532385 [PubMed]

Primary immunodeficiency and chronic mucocutaneous candidiasis: pathophysiological, diagnostic, and therapeutic approaches.

February 3, 2021 By Manish Butte

Primary immunodeficiency and chronic mucocutaneous candidiasis: pathophysiological, diagnostic, and therapeutic approaches.

Allergol Immunopathol (Madr). 2021;49(1):118-127

Authors: Egri N, Esteve-Solé A, Deyà-Martínez À, de Landazuri IO, Vlagea A, García AP, Cardozo C, Garcia-Vidal C, Bartolomé CS, Español-Rego M, Yiyi L, Bosch-Amate X, Ferrando J, Yagüe J, Juan M, Alsina L

Abstract
Chronic mucocutaneous candidiasis (CMC) is characterized by a chronic or recurrent non-invasive infection, mainly due to Candida albicans, in skin, nails, and mucous membranes, associated in some cases with autoimmune manifestations. The key immune defect is a disruption of the action of cytokine IL-17, whose most common genetic etiology is STAT1 gene gain-of-function (GOF) mutations. The initial appropriate treatment for fungal infections is with azoles. However, the frequent occurrence of drug resistance is the main limitation. Therefore, identification of the underlying inborn error if immunity in CMC may allow to widen therapeutic options aimed at restoring immunological function. Type I and II Janus kinase-inhibitors have been shown to control CMC in cases associated with STAT1 GOF. In this review, we delve into the pathogenesis of CMC and the underlying immune mechanisms. We describe the reported genetic defects in which CMC is the main manifestation. Diagnostic and therapeutic approaches for these patients are also offered.

PMID: 33528939 [PubMed – as supplied by publisher]

Daratumumab for delayed RBC engraftment following major ABO mismatched haploidentical bone marrow transplantation.

February 3, 2021 By Manish Butte

Daratumumab for delayed RBC engraftment following major ABO mismatched haploidentical bone marrow transplantation.

Transfusion. 2021 Feb 02;:

Authors: Yates B, Molloy E, Dulau-Florea A, Braylan R, Hogan L, Hickstein DD, Freeman AF, Kalsi SS, Shah NN

Abstract
BACKGROUND: Recent case reports have described the efficacy of daratumumab to treat refractory pure red cell aplasia (PRCA) following major ABO mismatched allogeneic hematopoietic stem cell transplantation (HSCT). In this report, we describe the use of daratumumab as a first-line agent for treatment of delayed red blood cell (RBC) engraftment following a major ABO mismatched pediatric HSCT and provide a review of the literature.
STUDY DESIGN AND MATERIALS: We report on a 14-year-old with DOCK8 deficiency who underwent a myeloablative, haploidentical bone marrow transplant from her major ABO mismatched sister (recipient O+, donor A+) for treatment of her primary immunodeficiency. Despite achieving full donor chimerism, she had delayed RBC engraftment requiring ongoing transfusions. Due to iron deposition, symptomatic anemia, and persistence of anti-A iso-hemagglutinins despite discontinuation of immunosuppression, treatment for delayed RBC engraftment with the CD38-targeted monoclonal antibody daratumumab was selected as a less immunosuppressive agent that could more selectively target iso-hemagglutinin producing plasma cells without causing broad B-cell aplasia.
RESULTS: Clinical effect with daratumumab was demonstrated by reduced iso-hemagglutinin titer, increased reticulocytosis, normalization of her hemoglobin, and transfusion independence. In the 11-month follow-up period to date, no additional transfusions or immunosuppression have been necessary, despite persistence of low-level anti-A iso-hemagglutinin.
CONCLUSION: Our experience suggests that daratumumab was an effective first-line therapy for delayed RBC engraftment and that earlier consideration for daratumumab in treatment of delayed RBC engraftment may be warranted.

PMID: 33528026 [PubMed – as supplied by publisher]

Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases.

February 3, 2021 By Manish Butte

Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases.

J Clin Immunol. 2021 Feb 01;:

Authors: Nishimura A, Aoki Y, Ishiwata Y, Ichimura T, Ueyama J, Kawahara Y, Tomoda T, Inoue M, Matsumoto K, Inoue K, Hiroki H, Ono S, Yamashita M, Okano T, Tanaka-Kubota M, Ashiarai M, Miyamoto S, Miyawaki R, Yamagishi C, Tezuka M, Okawa T, Hoshino A, Endo A, Yasuhara M, Kamiya T, Mitsuiki N, Ono T, Isoda T, Yanagimachi M, Tomizawa D, Nagasawa M, Mizutani S, Kajiwara M, Takagi M, Kanegane H, Imai K, Morio T

Abstract
PURPOSE: The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID).
METHODS: We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID.
RESULTS: The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival.
CONCLUSIONS: RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.

PMID: 33527309 [PubMed – as supplied by publisher]

Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis.

February 3, 2021 By Manish Butte

Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis.

PLoS Biol. 2020 12;18(12):e3000991

Authors: Shi Y, Liu Z, Zhang Q, Vallee I, Mo Z, Kishi S, Yang XL

Abstract
Hypoxia-induced angiogenesis maintains tissue oxygen supply and protects against ischemia but also enhances tumor progression and malignancy. This is mediated through activation of transcription factors like hypoxia-inducible factor 1 (HIF-1) and c-Myc, yet the impact of hypoxia on negative regulators of angiogenesis is unknown. During vascular development, seryl-tRNA synthetase (SerRS) regulates angiogenesis through a novel mechanism by counteracting c-Myc and transcriptionally repressing vascular endothelial growth factor A (VEGFA) expression. Here, we reveal that the transcriptional repressor role of SerRS is inactivated under hypoxia through phosphorylation by ataxia telangiectasia mutated (ATM) and ataxia telangiectasia mutated and RAD3-related (ATR) at Ser101 and Ser241 to attenuate its DNA binding capacity. In zebrafish, SerRSS101D/S241D, a phosphorylation-mimicry mutant, cannot suppress VEGFA expression to support normal vascular development. Moreover, expression of SerRSS101A/S241A, a phosphorylation-deficient and constitutively active mutant, prevents hypoxia-induced binding of c-Myc and HIF-1 to the VEGFA promoter, and activation of VEGFA expression. Consistently, SerRSS101A/S241A strongly inhibits normal and tumor-derived angiogenesis in mice. Therefore, we reveal a key step regulating hypoxic angiogenesis and highlight the importance of nuclear SerRS in post-developmental angiogenesis regulation in addition to vascular development. The role of nuclear SerRS in inhibiting both c-Myc and HIF-1 may provide therapeutic opportunities to correct dysregulation of angiogenesis in pathological settings.

PMID: 33351793 [PubMed – indexed for MEDLINE]

Complement factor H-deficient mice develop spontaneous hepatic tumors.

February 3, 2021 By Manish Butte

Icon for American Society for Clinical Investigation

Complement factor H-deficient mice develop spontaneous hepatic tumors.

J Clin Invest. 2020 08 03;130(8):4039-4054

Authors: Laskowski J, Renner B, Pickering MC, Serkova NJ, Smith-Jones PM, Clambey ET, Nemenoff RA, Thurman JM

Abstract
Hepatocellular carcinoma (HCC) is difficult to detect, carries a poor prognosis, and is one of few cancers with an increasing yearly incidence. Molecular defects in complement factor H (CFH), a critical regulatory protein of the complement alternative pathway (AP), are typically associated with inflammatory diseases of the eye and kidney. Little is known regarding the role of CFH in controlling complement activation within the liver. While studying aging CFH-deficient (fH-/-) mice, we observed spontaneous hepatic tumor formation in more than 50% of aged fH-/- males. Examination of fH-/- livers (3-24 months) for evidence of complement-mediated inflammation revealed widespread deposition of complement-activation fragments throughout the sinusoids, elevated transaminase levels, increased hepatic CD8+ and F4/80+ cells, overexpression of hepatic mRNA associated with inflammatory signaling pathways, steatosis, and increased collagen deposition. Immunostaining of human HCC biopsies revealed extensive deposition of complement fragments within the tumors. Investigating the Cancer Genome Atlas also revealed that increased CFH mRNA expression is associated with improved survival in patients with HCC, whereas mutations are associated with worse survival. These results indicate that CFH is critical for controlling complement activation in the liver, and in its absence, AP activation leads to chronic inflammation and promotes hepatic carcinogenesis.

PMID: 32369457 [PubMed – indexed for MEDLINE]

Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome.

February 3, 2021 By Manish Butte

Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome.

J Clin Invest. 2020 08 03;130(8):4167-4181

Authors: Dmitrieva NI, Walts AD, Nguyen DP, Grubb A, Zhang X, Wang X, Ping X, Jin H, Yu Z, Yu ZX, Yang D, Schwartzbeck R, Dalgard CL, Kozel BA, Levin MD, Knutsen RH, Liu D, Milner JD, López DB, O’Connell MP, Lee CR, Myles IA, Hsu AP, Freeman AF, Holland SM, Chen G, Boehm M

Abstract
There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, also known as Job’s syndrome) is caused by mutations in STAT3. These patients present with immunodeficiency accompanied by severe nonimmunological features, including skeletal, connective tissue, and vascular abnormalities, poor postinfection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here, we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delayed granulation tissue formation and vascularization during skin-wound healing in AD-HIES patients. Global gene expression analysis in AD-HIES patient skin fibroblasts identified deficiencies in a STAT3-controlled transcriptional network regulating extracellular matrix (ECM) remodeling and angiogenesis, with hypoxia-inducible factor 1α (HIF-1α) being a major contributor. Consistent with this, histological analysis of skin wounds and coronary arteries from AD-HIES patients showed decreased HIF-1α expression and revealed abnormal organization of the ECM and altered formation of the coronary vasa vasorum. Disease modeling using cell culture and mouse models of angiogenesis and wound healing confirmed these predicted deficiencies and demonstrated therapeutic benefit of HIF-1α-stabilizing drugs. The study provides mechanistic insights into AD-HIES pathophysiology and suggests potential treatment options for this rare disease.

PMID: 32369445 [PubMed – indexed for MEDLINE]

The Association of Gut Microbiota and Treg Dysfunction in Autoimmune Diseases.

February 2, 2021 By Manish Butte

The Association of Gut Microbiota and Treg Dysfunction in Autoimmune Diseases.

Adv Exp Med Biol. 2021;1278:191-203

Authors: Liu Y, Tran DQ, Lindsey JW, Rhoads JM

Abstract
Autoimmune conditions affect 23 million Americans or 7% of the US population. There are more than 100 autoimmune disorders, affecting every major organ system in humans. This chapter aims to further explain Treg dysfunction autoimmune disorders, including monogenic primary immune deficiency such as immune dysregulation polyendocrinopathy, enteropathy, X-linked inheritance (IPEX) syndrome, and polygenic autoimmune diseases with Treg dysfunction such as multiple sclerosis (MS), inflammatory bowel disease (IBD), and food allergy. These conditions are associated with an abnormal small intestinal and colonic microbiome. Some disorders clearly improve with therapies aimed at microbial modification, including probiotics and fecal microbiota transplantation (FMT). Approaches to prevent and treat these disorders will need to focus on the acquisition and maintenance of a healthy colonic microbiota, in addition to more focused approaches at immune suppression during acute disease exacerbations.

PMID: 33523449 [PubMed – as supplied by publisher]

Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome.

February 2, 2021 By Manish Butte

Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome.

J Clin Immunol. 2021 Feb 01;:

Authors: Harrison SC, Tsilifis C, Slatter MA, Nademi Z, Worth A, Veys P, Ponsford MJ, Jolles S, Al-Herz W, Flood T, Cant AJ, Doffinger R, Barcenas-Morales G, Carpenter B, Hough R, Haraldsson Á, Heimall J, Grimbacher B, Abinun M, Gennery AR

Abstract
Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.

PMID: 33523338 [PubMed – as supplied by publisher]