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B Lymphocyte-Specific Loss of Ric-8A Results in a Gα Protein Deficit and Severe Humoral Immunodeficiency.

August 2, 2015 By Manish Butte

B Lymphocyte-Specific Loss of Ric-8A Results in a Gα Protein Deficit and Severe Humoral Immunodeficiency.

J Immunol. 2015 Jul 31;

Authors: Boularan C, Hwang IY, Kamenyeva O, Park C, Harrison K, Huang Z, Kehrl JH

Abstract
Resistance to inhibitors of cholinesterase 8A (Ric-8A) is a highly evolutionarily conserved cytosolic protein initially identified in Caenorhabditis elegans, where it was assigned a regulatory role in asymmetric cell divisions. It functions as a guanine nucleotide exchange factor for Gαi, Gαq, and Gα12/13 and as a molecular chaperone required for the initial association of nascent Gα subunits with cellular membranes in embryonic stem cell lines. To test its role in hematopoiesis and B lymphocytes specifically, we generated ric8(fl/fl)vav1-cre and ric8(fl/fl)mb1-cre mice. The major hematopoietic cell lineages developed in the ric8(fl/fl)vav1-cre mice, notwithstanding severe reduction in Gαi2/3, Gαq, and Gα13 proteins. B lymphocyte-specific loss of Ric-8A did not compromise bone marrow B lymphopoiesis, but splenic marginal zone B cell development failed, and B cells underpopulated lymphoid organs. The ric8(fl/fl)mb1-cre B cells exhibited poor responses to chemokines, abnormal trafficking, improper in situ positioning, and loss of polarity components during B cell differentiation. The ric8(fl/fl)mb1-cre mice had a severely disrupted lymphoid architecture and poor primary and secondary Ab responses. In B lymphocytes, Ric-8A is essential for normal Gα protein levels and is required for B cell differentiation, trafficking, and Ab responses.

PMID: 26232433 [PubMed – as supplied by publisher]

Streptococcus pneumoniae antibody titres in patients with primary antibody deficiency receiving intravenous immunoglobulin (IVIG) compared to subcutaneous immunoglobulin (SCIG).

August 1, 2015 By Manish Butte

Streptococcus pneumoniae antibody titres in patients with primary antibody deficiency receiving intravenous immunoglobulin (IVIG) compared to subcutaneous immunoglobulin (SCIG).

Clin Exp Immunol. 2015 Jun 9;

Authors: Knutsen AP, Leiva LE, Caruthers C, Rodrigues J, Sorensen RU

Abstract
Intravenous immunoglobulin (IVIG) and subcutaneous immunoglobulin (SCIG) are effective in the treatment of patients with primary antibody deficiency disorders (PAD). The purpose of this study was to evaluate Streptococcus pneumoniae (Spn) antibody titres to 14 serotypes in patients receiving IVIG compared to SCIG and to correlate Spn antibody levels to clinical outcome. The doses of immunoglobulin (Ig)G/kg/month were similar in both IVIG and SCIG groups. In 11 patients treated with IVIG, Spn antibody titres were ≥ 1·3 μg/ml to 99·4 ± 2·1% of the 14 serotypes at peak IVIG but decreased to 66·9 ± 19·8% at trough IVIG. Loss of Spn titres ≥ 1·3 μg/ml was most frequent for Spn serotypes 1, 4, 9V and 23. This correlated with lower Spn antibody titres to these serotypes at peak IVIG compared to the other serotypes. In 13 patients treated with SCIG, Spn antibody titres were protective to 58·2 ± 23·3% of the serotypes 3-5 days after infusion, similar to trough IVIG. Similarly, the Spn serotypes with the least protective percentages were the same as the ones observed in trough IVIG. There were no annualized serious bacterial infections (aSBI) in either group. However, there were significantly decreased annualized other infections (aOI) in the SCIG group compared to the IVIG-treated group, 0·8 ± 0·7 versus 2·2 ± 1·2 infections/patient/year (P = 0·004). Breakthrough aOI did not correlate with protective or higher serum Spn antibody titres.

PMID: 26230522 [PubMed – as supplied by publisher]

Immunodeficiency and severe susceptibility to bacterial infection associated with a loss-of-function homozygous mutation of MKL1.

August 1, 2015 By Manish Butte

Immunodeficiency and severe susceptibility to bacterial infection associated with a loss-of-function homozygous mutation of MKL1.

Blood. 2015 Jul 29;

Authors: Record J, Malinova D, Zenner HL, Plagnol V, Nowak K, Syed F, Bouma G, Curtis J, Gilmour K, Cale C, Hackett S, Charras G, Moulding D, Nejentsev S, Thrasher AJ, Burns SO

Abstract
Megakaryoblastic Leukemia 1 (MKL1), also known as MAL or MRTF-A, is a co-activator of serum response factor (SRF), regulating transcription of actin and actin cytoskeleton-related genes. MKL1 is known to be important for megakaryocyte differentiation and function in mice but its role in immune cells is unexplored. Here we report a patient with a homozygous nonsense mutation in the MKL1 gene resulting in immunodeficiency characterised predominantly by susceptibility to severe bacterial infection. We show that loss of MKL1 protein expression causes a dramatic loss of F-actin content in lymphoid and myeloid lineage immune cells and widespread cytoskeletal dysfunction. MKL1-deficient neutrophils displayed reduced phagocytosis and almost complete abrogation of migration in vitro. Similarly, primary dendriritic cells were unable to spread normally or to form podosomes. Silencing of MKL1 in myeloid cell lines revealed that F-actin assembly was abrogated through reduction of G-actin levels and disturbed expression of multiple actin-regulating genes. Impaired migration of these cells was associated with failure of uropod retraction likely due to altered contractility and adhesion, evidenced by reduced expression of the MYL9 component of myosin II complex and over expression of CD11b integrin. Together, our results show that MKL1 is a non-redundant regulator of cytoskeleton-associated functions in immune cells and fibroblasts and that its depletion underlies a novel human primary immunodeficiency.

PMID: 26224645 [PubMed – as supplied by publisher]

Atopic dermatitis in children: clinical features, pathophysiology, and treatment.

August 1, 2015 By Manish Butte

Atopic dermatitis in children: clinical features, pathophysiology, and treatment.

Immunol Allergy Clin North Am. 2015 Feb;35(1):161-83

Authors: Lyons JJ, Milner JD, Stone KD

Abstract
Atopic dermatitis (AD) is a chronic, relapsing, highly pruritic skin condition resulting from disruption of the epithelial barrier and associated immune dysregulation in the skin of genetically predisposed hosts. AD generally develops in early childhood, has a characteristic age-dependent distribution and is commonly associated with elevated IgE, peripheral eosinophilia, and other allergic diseases. Medications such as antihistamines have demonstrated poor efficacy in controlling AD-associated itch. Education of patients regarding the primary underlying defects and provision of a comprehensive skin care plan is essential for disease maintenance and management of flares.

PMID: 25459583 [PubMed – indexed for MEDLINE]

p38 Mitogen-Activated Protein Kinase in beryllium-induced dendritic cell activation.

August 1, 2015 By Manish Butte

p38 Mitogen-Activated Protein Kinase in beryllium-induced dendritic cell activation.

Hum Immunol. 2014 Dec;75(12):1155-62

Authors: Li L, Huang Z, Gillespie M, Mroz PM, Maier LA

Abstract
Dendritic cells (DC) play a role in the regulation of immune responses to haptens, which in turn impact DC maturation. Whether beryllium (Be) is able to induce DC maturation and if this occurs via the MAPK pathway is not known. Primary monocyte-derived DCs (moDCs) models were generated from Be non-exposed healthy volunteers as a non-sensitized cell model, while PBMCs from BeS (Be sensitized) and CBD (chronic beryllium disease) were used as disease models. The response of these cells to Be was evaluated. The expression of CD40 was increased significantly (p<0.05) on HLA-DP Glu69+ moDCs after 100 μM BeSO₄-stimulation. BeSO₄ induced p38MAPK phosphorylation, while IκB-α was degraded in Be-stimulated moDCs. The p38 MAPK inhibitor SB203580 blocked Be-induced NF-κB activation in moDCs, suggesting that p38MAPK and NF-κB are dependently activated by BeSO₄. Furthermore, in BeS and CBD subjects, SB203580 downregulated Be-stimulated proliferation in a dose-dependent manner, and decreased Be-stimulated TNF-α and IFNγ cytokine production. Taken together, this study suggests that Be-induces non-sensitized Glu69+ DCs maturation, and that p38MAPK signaling is important in the Be-stimulated DCs activation as well as subsequent T cell proliferation and cytokine production in BeS and CBD. In total, the MAPK pathway may serve as a potential therapeutic target for human granulomatous lung diseases.

PMID: 25454621 [PubMed – indexed for MEDLINE]

Efficacy of subcutaneous immunoglobulins in primary immunodeficiency with Crohn's-like phenotype: report of a case.

July 30, 2015 By Manish Butte

Efficacy of subcutaneous immunoglobulins in primary immunodeficiency with Crohn’s-like phenotype: report of a case.

Eur Rev Med Pharmacol Sci. 2015 Jul;19(14):2641-2645

Authors: Sanges M, Spadaro G, Miniero M, Mattera D, Sollazzo R, D’Armiento FP, De Palma GD, Pecoraro A, Borrelli F, Genovese A, D’Arienzo A

Abstract
Common variable immune deficiency (CVID) is the most frequent primary immunodeficiency in adults. In CVID, the prevalence of gastrointestinal manifestations ranges between 2 and 50% with a complication-related morbidity second only to that of the respiratory tract. In some cases, clinical and endoscopic features are undistinguishable from those of inflammatory bowel disease (IBD). We describe the case of a 28-year-old man in which a diagnosis of Crohn’s disease was firstly suspected. Subsequently, a diagnosis of Crohn’s-like disease in a patient with CVID was made and a replacement therapy with human normal immunoglobulin intravenously was started. Unfortunately, serum IgG levels remained below 2.0 g/l in pre-infusional controls with persistence of gastrointestinal symptoms and malnutrition despite anti-inflammatory therapy (mesalazine, corticosteroids). Then, the patient began treatment with human normal immunoglobulins administered subcutaneously. The follow-up visits showed a progressive increase in serum IgG. Moreover, the patient reported improvement of gastrointestinal symptoms with reduction of diarrhoea, and laboratory tests showed a progressive and significant improvement. We confirm that therapy with subcutaneously administered immunoglobulins is safe and effective. In addition, our observations indicate that, for patients with CVID and enteropathic complications, replacement therapy with subcutaneous IgG may be the treatment of choice.

PMID: 26221895 [PubMed – as supplied by publisher]

An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation.

July 30, 2015 By Manish Butte

An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation.

J Allergy Clin Immunol. 2015 Jul 25;

Authors: Le Guen T, Touzot F, André-Schmutz I, Lagresle-Peyrou C, France B, Kermasson L, Lambert N, Picard C, Nitschke P, Carpentier W, Bole-Feysot C, Lim A, Cavazzana M, Callebaut I, Soulier J, Jabado N, Fischer A, de Villartay JP, Revy P

Abstract
BACKGROUND: Myb-Like, SWIRM, and MPN domains 1 (MYSM1) is a metalloprotease that deubiquitinates the K119-monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene transcription silencing. Likewise, it has been reported that murine Mysm1 participates in transcription derepression of genes, among which are transcription factors involved in hematopoietic stem cell homeostasis, hematopoiesis, and lymphocyte differentiation. However, whether MYSM1 has a similar function in human subjects remains unclear. Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities.
OBJECTIVES: We sought to characterize the underlying genetic cause of this syndrome.
METHODS: We performed genome-wide homozygosity mapping, followed by whole-exome sequencing.
RESULTS: Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain. Remarkably, during the course of our study, the patient recovered a normal immunohematologic phenotype. Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell.
CONCLUSIONS: We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects. In addition, we describe one of the few examples of spontaneous in vivo genetic cure of a human immunodeficiency.

PMID: 26220525 [PubMed – as supplied by publisher]

Hyper-IgE syndromes: recent advances in pathogenesis, diagnostics and clinical care.

July 30, 2015 By Manish Butte

Hyper-IgE syndromes: recent advances in pathogenesis, diagnostics and clinical care.

Curr Opin Hematol. 2015 Jan;22(1):12-22

Authors: Farmand S, Sundin M

Abstract
PURPOSE OF REVIEW: This review provides an overview on recent data regarding pathogenesis, diagnostics and clinical care of hyper-IgE syndromes (HIES). HIES are a group of primary immunodeficiencies with overlapping and distinct features, most frequently caused by deficiency in signal transducer and activator of transcription 3 (STAT3) or dedicator of cytokinesis 8 (DOCK8).
RECENT FINDINGS: Particular progress has been made in deciphering the relevance of STAT3 and DOCK8 for B-cell, T-cell and natural killer-cell immunity as well as in understanding allergic features. Multisystemic features of STAT3-deficient HIES, for example, recurrent fractures and osteopenia, a high degree of vasculopathy and brain white matter hyperintensities, have been thoroughly characterized. IgG replacement may add to the clinical care in STAT3-deficient HIES. In DOCK8-deficient HIES, the high morbidity and deaths in early age seem to justify allogeneic hematopoietic stem cell transplantation. New HIES entities have also been reported.
SUMMARY: The recent advances expand our understanding of HIES, and improve the diagnostics and clinical care. Yet, more research is required to fully elucidate the specific infection susceptibilities and lung complications, particularly in STAT3-deficient HIES. Future studies also need to focus on clinical care and treatment of nonimmunologic features of HIES, as well as on exploring curative treatments.

PMID: 25469836 [PubMed – indexed for MEDLINE]

Leukocyte adhesion deficiency type III: clinical features and treatment with stem cell transplantation.

July 29, 2015 By Manish Butte

Leukocyte adhesion deficiency type III: clinical features and treatment with stem cell transplantation.

J Pediatr Hematol Oncol. 2015 May;37(4):264-8

Authors: Stepensky PY, Wolach B, Gavrieli R, Rousso S, Ben Ami T, Goldman V, Rozovsky K, Hanna S, Etzioni A, Weintraub M

Abstract
Leukocyte adhesion deficiency type III (LADIII) is an autosomal recessive disorder that presents with a severe leukocyte adhesion defect and a Glanzmann-type thrombocytopathy. Hematopoietic stem cell transplantation (HSCT)–the only definitive treatment for LADIII–appears to have a high rate of complications. In this study, we describe a new group of patients with LADIII, highlighting further clinical and immunologic aspects of this disease, and reevaluating the effectiveness of HSCT for its treatment. The patients had clinical and laboratory findings consistent with LADIII. Molecular analysis confirmed the presence of a mutation in the kindlin-3 gene. HSCT was carried out in 3 patients and was successful in 2. The diagnosis of LADIII should be considered in all patients who present with recurrent infections and a bleeding diathesis, regardless of the leukocyte count. LADIII is a primary immune deficiency, which can be successfully corrected by bone marrow transplantation if applied early in the course of the disease using appropriate conditioning.

PMID: 25072369 [PubMed – indexed for MEDLINE]

Eosinophilia Associated with Disorders of Immune Deficiency or Immune Dysregulation.

July 27, 2015 By Manish Butte

Eosinophilia Associated with Disorders of Immune Deficiency or Immune Dysregulation.

Immunol Allergy Clin North Am. 2015 Aug;35(3):523-544

Authors: Williams KW, Milner JD, Freeman AF

Abstract
Increased serum eosinophil levels have been associated with multiple disorders of immune deficiency or immune dysregulation. Although primary immunodeficiency diseases are rare, it is important to consider these in the differential diagnosis of patients with eosinophilia. In this review, the clinical features, laboratory findings, diagnosis, and genetic basis of disease of several disorders of immune deficiency or dysregulation are discussed. The article includes autosomal dominant hyper IgE syndrome, DOCK8 deficiency, phosphoglucomutase 3 deficiency, ADA-SCID, Omenn syndrome, Wiskott-Aldrich syndrome, Loeys-Dietz syndrome, autoimmune lymphoproliferative syndrome, immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, Comel-Netherton syndrome, and severe dermatitis, multiple allergies, and metabolic wasting syndrome.

PMID: 26209898 [PubMed – as supplied by publisher]