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End-stage renal disease secondary to anti-glomerular basement membrane disease in a child with common variable immunodeficiency.

March 7, 2019 By Manish Butte

End-stage renal disease secondary to anti-glomerular basement membrane disease in a child with common variable immunodeficiency.

Clin Nephrol Case Stud. 2019;7:1-6

Authors: Mannemuddhu SS, Clapp W, Modica R, Elder ME, Upadhyay K

Abstract
BACKGROUND: Anti-glomerular basement membrane (GBM) disease is caused by autoantibodies against the α3-chain of type IV collagen in the GBM. Common variable immunodeficiency (CVID) is a primary immunodeficiency manifested by hypogammaglobulinemia, inability to make functional antibody, and recurrent infections. This report extends the phenotype of CVID-associated autoimmune diseases to include anti-GBM disease.
CASE PRESENTATION: A 15-year-old Caucasian female with prior normal renal function presented with nephrotic proteinuria, pedal edema, oliguria, acute kidney injury, and was found to have positive serum anti-GBM antibody. She had been diagnosed with CVID at 3 years of age. Her renal biopsy showed crescentic glomerulonephritis (50%), and immunofluorescence showed linear staining for IgG along the glomerular capillary wall. There was no clinical or imaging evidence of pulmonary hemorrhage. She was treated with pulse IV steroids, cyclophosphamide, rituximab, and several sessions of plasmapheresis. Her serum anti-GBM antibody level decreased from 194 U/mL at presentation to 0 U/mL after therapy. However, she progressed to end-stage renal disease (ESRD) within weeks, despite aggressive therapy, and required chronic renal replacement therapy in the form of dialysis. Her clinical course was also complicated by hypertensive encephalopathy, CMV viremia and meningoencephalitis, status epilepticus, and she passed away a few months later from lower respiratory tract complications.
CONCLUSION: Anti-GBM disease is a rare autoimmune condition that has not been reported in association with a primary immunodeficiency syndrome. ESRD secondary to anti-GBM disease in a patient with CVID is an interesting association and supports the role of immune dysregulation in systemic autoimmune disease.

PMID: 30838168 [PubMed]

Type I leucocyte adhesion deficiency in Yemenian family managed with appropriate treatment: a case series.

March 6, 2019 By Manish Butte

Type I leucocyte adhesion deficiency in Yemenian family managed with appropriate treatment: a case series.

Dermatol Ther. 2019 Mar 05;:e12864

Authors: Cantisani C, Naqeshbandi AF, Goldust M, Lampitelli S, Cantoresi F, Alsorori E

Abstract
Primary immunodeficiencies(PIDS) are rare,inherited diseases, characterized by altered function or absence of immune cells. Among them is leukocyte adhesion deficiency type I (LAD-I), an autosomal recessive disorder characterized by primary immunodeficiency, caused by mutations in the ITGB2 gene which produces inability of leucocytes to migrate towards the area of inflammation and is associated with recurrent life-threatening bacterial and fungal infections. Pyoderma gangrenosum(PG) is an uncommon noninfectious neutrophilic dermatosis, characterized by recurrent, necrotic ulcers. It is a diagnosis of exclusion and can be challenging and its management is empirical, with local(topical tacrolimus or intralesional triamcinolone) or systemic immunosuppressive therapy (oral or intravenous glucocorticoids, sulfasalazine, especially in cases associated with crohn’s disease, cyclosporine and, recently, anti-TNF drugs such as Infliximab, Etanercept, Adalimumab). Though skin ulcerations are common, predominant clinical presentation as PG can often mimic other diseases. It is unusual in children even more in LAD-I. Here we present a Yemenian family with LAD-I from consanguineous relatives. All patients had history of chronic recurrent skin ulcerations without any bleeding tendency, associated with persistent neutrophilia and requiring steroids and antibiotics. There was no history of delayed cord separation and the condition was initially diagnosed as epidermolysis bullosa, but successively as PG. LAD-I should be kept in mind while evaluating patients with PG especially in children with persistent neutrophilia in the absence of other rheumatological disorders. Its diagnosis is extremely important from the management perspective, as treating these patients without adequate antibiotic cover may be fatal, as happened to one of our patient, and these patients often require hematopoietic stem cell transplantation for permanent cure. Therefore, genetic counseling especially in population with high consanguinity is mandatory. This article is protected by copyright. All rights reserved.

PMID: 30834665 [PubMed – as supplied by publisher]

Primary Immunodeficiency: New Approaches in Genetic Diagnosis, and Constructing Targeted Therapies.

March 6, 2019 By Manish Butte

Primary Immunodeficiency: New Approaches in Genetic Diagnosis, and Constructing Targeted Therapies.

J Allergy Clin Immunol Pract. 2019 Mar;7(3):839-841

Authors: Ziegler JB, Ballow M

PMID: 30832894 [PubMed – in process]

Hematopoietic Stem Cell Transplantation Beyond Severe Combined Immunodeficiency: Seeking a Cure for Primary Immunodeficiency.

March 6, 2019 By Manish Butte

Hematopoietic Stem Cell Transplantation Beyond Severe Combined Immunodeficiency: Seeking a Cure for Primary Immunodeficiency.

J Allergy Clin Immunol Pract. 2019 Mar;7(3):776-785

Authors: Mitchell R

Abstract
Hematopoietic stem cell transplantation (HSCT) can provide definitive therapy for patients with primary immunodeficiency disease (PIDD). Modern HSCT techniques and supportive care have significantly improved outcomes for patients with PIDD. This review examines current HSCT practice for PIDD other than severe combined immunodeficiency, and explores indications, risks, and long-term outcomes for this group of challenging diseases.

PMID: 30832892 [PubMed – in process]

Mechanism-Based Precision Therapy for the Treatment of Primary Immunodeficiency and Primary Immunodysregulatory Diseases.

March 6, 2019 By Manish Butte

Mechanism-Based Precision Therapy for the Treatment of Primary Immunodeficiency and Primary Immunodysregulatory Diseases.

J Allergy Clin Immunol Pract. 2019 Mar;7(3):761-773

Authors: Leiding JW, Forbes LR

Abstract
Advances in understanding the mechanism, immunobiology, and pathophysiology of primary immunodeficiency diseases have created opportunities for the use of precision medicines for the treatment of disease-related manifestations. Modulation of the immune system to treat autoimmunity began with the use of intravenous immunoglobulin, improved with the development of monoclonal antibodies, and has now become standard in certain diseases with mechanistic-based targets that alter the molecular mechanism of disease. In this article, we review targeted therapies for disorders of hyperinflammation, primary immunodysregulatory diseases, and primary immunodeficiencies. We also look to the future where gene editing will tailor therapy in an even more precise way for each individual disease and patient.

PMID: 30832891 [PubMed – in process]

Mechanism of dysfunction of human variants of the IRAK4 kinase and a role for its kinase activity in interleukin-1 receptor signaling.

March 5, 2019 By Manish Butte

Mechanism of dysfunction of human variants of the IRAK4 kinase and a role for its kinase activity in interleukin-1 receptor signaling.

J Biol Chem. 2018 09 28;293(39):15208-15220

Authors: De S, Karim F, Kiessu E, Cushing L, Lin LL, Ghandil P, Hoarau C, Casanova JL, Puel A, Rao VR

Abstract
Interleukin-1 receptor (IL1R)-associated kinase 4 (IRAK4) is a central regulator of innate immune signaling, controlling IL1R and Toll-like receptor (TLR)-mediated responses and containing both scaffolding and kinase activities. Humans deficient in IRAK4 activity have autosomal recessive primary immune deficiency (PID). Here, we characterized the molecular mechanism of dysfunction of two IRAK4 PID variants, G298D and the compound variant R12C (R12C/R391H/T458I). Using these variants and the kinase-inactive D329A variant to delineate the contributions of IRAK4’s scaffolding and kinase activities to IL1R signaling, we found that the G298D variant is kinase-inactive and expressed at extremely low levels, acting functionally as a null mutation. The R12C compound variant possessed WT kinase activity, but could not interact with myeloid differentiation primary response 88 (MyD88) and IRAK1, causing impairment of IL-1-induced signaling and cytokine production. Quantitation of IL-1 signaling in IRAK4-deficient cells complemented with either WT or the R12C or D329A variant indicated that the loss of MyD88 interaction had a greater impact on IL-1-induced signaling and cytokine expression than the loss of IRAK4 kinase activity. Importantly, kinase-inactive IRAK4 exhibited a greater association with MyD88 and a weaker association with IRAK1 in IRAK4-deficient cells expressing kinase-inactive IRAK4 and in primary cells treated with a selective IRAK4 inhibitor. Loss of IRAK4 kinase activity only partially inhibited IL-1-induced cytokine and NF-κB signaling. Therefore, the IRAK4-MyD88 scaffolding function is essential for IL-1 signaling, but IRAK4 kinase activity can control IL-1 signal strength by modulating the association of IRAK4, MyD88, and IRAK1.

PMID: 30115681 [PubMed – indexed for MEDLINE]

Transcriptome profiling of monocytes from XLA patients revealed the innate immune function dysregulation due to the BTK gene expression deficiency.

March 5, 2019 By Manish Butte

Transcriptome profiling of monocytes from XLA patients revealed the innate immune function dysregulation due to the BTK gene expression deficiency.

Sci Rep. 2017 07 28;7(1):6836

Authors: Mirsafian H, Ripen AM, Leong WM, Chear CT, Bin Mohamad S, Merican AF

Abstract
X-linked agammaglobulinemia (XLA) is a rare genetic disorder, caused by mutations in BTK (Bruton’s Tyrosine Kinase) gene. Deep high-throughput RNA sequencing (RNA-Seq) approach was utilized to explore the possible differences in transcriptome profiles of primary monocytes in XLA patients compared with healthy subjects. Our analysis revealed the differences in expression of 1,827 protein-coding genes, 95 annotated long non-coding RNAs (lncRNAs) and 20 novel lincRNAs between XLA patients and healthy subjects. GO and KEGG pathway analysis of differentially expressed (DE) protein-coding genes showed downregulation of several innate immune-related genes and upregulation of oxidative phosphorylation and apoptosis-related genes in XLA patients compared to the healthy subjects. Moreover, the functional prediction analysis of DE lncRNAs revealed their potential role in regulating the monocytes cell cycle and apoptosis in XLA patients. Our results suggested that BTK mutations may contribute to the dysregulation of innate immune system and increase susceptibility to apoptosis in monocytes of XLA patients. This study provides significant finding on the regulation of BTK gene in monocytes and the potential for development of innovative biomarkers and therapeutic monitoring strategies to increase the quality of life in XLA patients.

PMID: 28754963 [PubMed – indexed for MEDLINE]

Impaired control of multiple virus infections in a family with complete IRF9 deficiency.

March 4, 2019 By Manish Butte

Impaired control of multiple virus infections in a family with complete IRF9 deficiency.

J Allergy Clin Immunol. 2019 Feb 28;:

Authors: García-Morato MB, Apalategi AC, Bravo-Gallego LY, Moreno AB, Simón-Fuentes M, Garmendia JV, Echevarría AM, Rabes TDR, Domínguez-Soto Á, López-Granados E, Reyburn HT, Pena RR

Abstract
We report a kindred deficient in IRF9. The absence of this factor inactivates the interferon response and provokes a marked susceptibility to infection with both RNA and DNA viruses.

PMID: 30826365 [PubMed – as supplied by publisher]

T cell mitochondrial dysfunction and lymphopenia in DOCK2-deficient patients.

March 4, 2019 By Manish Butte

T cell mitochondrial dysfunction and lymphopenia in DOCK2-deficient patients.

J Allergy Clin Immunol. 2019 Feb 28;:

Authors: Alosaimi MF, Shendi H, Beano A, Stafstrom K, El Hawary R, Meshaal S, Galal N, Pai SY, El-Marsafy A, Geha RS, Chou J

Abstract
This study delineates the mitochondrial defects in DOCK2-deficient T cells contributing to the T cell lymphopenia characteristic of this primary immunodeficiency.

PMID: 30826364 [PubMed – as supplied by publisher]

Defects in memory B-cell and plasma cell subsets expressing different immunoglobulin-subclasses in CVID and Ig-subclass deficiencies.

March 4, 2019 By Manish Butte

Defects in memory B-cell and plasma cell subsets expressing different immunoglobulin-subclasses in CVID and Ig-subclass deficiencies.

J Allergy Clin Immunol. 2019 Feb 28;:

Authors: Blanco E, Pérez-Andrés M, Arriba-Méndez S, Serrano C, Criado I, Pino-Molina LD, Silva S, Madruga I, Bakardjieva M, Martins C, Caetano AS, Romero A, Contreras-Sanfeliciano T, Bonroy C, Sala F, Martín A, Bastida JM, Lorente F, Prieto C, Dávila I, Marcos M, Kalina T, Vlkova M, Chevankova Z, Cordeiro AI, Philippé J, Haerynck F, López-Granados E, da Sousa AE, van der Burg M, van Dongen JJM, Orfao A, EuroFlow PID group

Abstract
BACKGROUND: Predominantly antibody deficiencies (PAD) are the most prevalent primary immune deficiencies, but their B-cell defects and underlying genetic alterations remain largely unknown.
OBJECTIVE: We investigated PAD patients for the distribution of 41 blood B-cell and plasma cell (PC) subsets, including subsets defined by expression of distinct immunoglobulin heavy chain (IgH) subclasses.
METHODS: Blood samples from 139 PAD patients -61 common variable immunodeficiency (CVID), 68 selective IgA-deficiency (IgAdef) and 10 IgG-subclass deficiency with IgA deficiency (IgG/Adef)- and 223 age-matched controls were studied by flowcytometry using EuroFlow Ig-isotype stainings. Patients were classified according to their B-cell and PC immune profile and the obtained patient clusters were correlated with clinical manifestations of PAD.
RESULTS: Decreased counts of blood PCs and/or memory B-cells (MBCs) expressing distinct IgA- and IgG-subclasses were identified in all PAD patients. In IgAdef patients, B-cell defects were mainly restricted to surface-membrane(sm)IgA+ PCs and MBCs with two clear subgroups showing strongly decreased smIgA+PCs with mild vs. severe smIgA+MBCs defects and higher frequencies of non-respiratory infections, autoimmunity, and affected family members. IgG/Adef and CVID patients showed defects in both smIgA+ and smIgG+ MBCs and PCs. Reduced switched-PCs were systematically found in CVID (absent in 98%) with six different defective MBC (and clinical) profiles: i) profound decrease of MBCs; ii) defective CD27+MBCs with almost normal IgG3+MBCs; iii) absence of switched-MBCs; and iv) presence of both unswitched and switched-MBCs without and; v) with IgG2+MBCs; and vi) with IgA1+MBCs.
CONCLUSION: Distinct PAD defective B-cell patterns were identified which are associated with unique clinical profiles.

PMID: 30826363 [PubMed – as supplied by publisher]