| 1. |
- Brodszki, Nicholas, et al.
(författare)
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Immune responses following meningococcal serogroups A, C, Y and W polysaccharide vaccination in C2-deficient persons: Evidence for increased levels of serum bactericidal antibodies.
- 2015
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Ingår i: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 33:15, s. 1839-1845
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Tidskriftsartikel (refereegranskat)abstract
- Complement C2 deficiency (C2D) is associated with immunological diseases and increased susceptibility to invasive infections caused by encapsulated bacteria such as Neisseria menigitidis. In this study we evaluate the immunogenicity of vaccination against N. menigitidis in C2D. C2D patients (n=22) and controls (n=52) were given a tetravalent meningococcal polysaccharide vaccine. Serum bactericidal antibody (SBA) titres (serogroups A, C, Y and W) were analysed using a rabbit complement source. Levels of IgG, IgM, and IgA, factor B, and factor H, polymorphisms of MBL and Fc-gamma receptors were determined. The C2D patients responded with an increased SBA titre to all four serogroups (p<0.001). The response rates define as SBA titres ≥8 were found to be between 85.7% and 92.5%. The post-vaccination titres for serogroups C, Y and W were equal to healthy controls. C2D patients with a history of invasive infection had a lower post-vaccination SBA titres both compared to healthy C2D persons (p=0.03) and compared to controls (p<0.0001). We found that the G2M*n/G2M*n genotype were associated with a higher SBA titres after immunization (p=0.03). None of the other investigated immunological factors appear to be important in influencing the vaccine responses. Autoimmune diseases in C2D did not affect the vaccine response. In general, vaccination against meningococci gave rise to antibody responses in the C2D patients that equal healthy controls. The response rate was lower to serogroup A and among C2D patients with history of invasive infections. The presence of G2M*n/G2M*n genotype was associated with higher SBA titres after immunization.
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| 2. |
- Brodszki, Nicholas, et al.
(författare)
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Novel Genetic Mutations in the First Swedish Patient with Purine Nucleoside Phosphorylase Deficiency and Clinical Outcome After Hematopoietic Stem Cell Transplantation with HLA-Matched Unrelated Donor.
- 2015
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Ingår i: JIMD Reports. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 2192-8304. ; 24, s. 9-83
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Tidskriftsartikel (refereegranskat)abstract
- Purine nucleoside phosphorylase (PNP) is an enzyme active in the purine salvage pathway. PNP deficiency caused by autosomal recessive mutations in the PNP gene leads to severe combined immunodeficiency (SCID) and in two thirds of cases also to neurological effects such as developmental delay, ataxia, and motor impairment.PNP deficiency has a poor outcome, and the only curative treatment is allogenic hematopoietic stem cell transplantation (HSCT). We present the first Swedish patient with PNP deficiency with novel mutations in the PNP gene and the immunological results of the HSCT and evaluate the impact of HSCT on the neurological symptoms. The patient presented early in life with neurological symptoms and suffered later from repeated serious respiratory tract infections. Biochemical tests showed severe reduction in PNP activity (1% residual activity). Genetic testing revealed two new mutations in the PNP gene: c.729C>G (p.Asn243Lys) and c.746A>C (p.Tyr249Cys). HSCT was performed with an unrelated donor, resulting in prompt and sustained engraftment and complete donor chimerism. There was no further aggravation of the patient's neurological symptoms at 21 months post HSCT, and appropriate developmental milestones were achieved. HSCT is curative for the immunological defect caused by PNP deficiency, and our case strengthens earlier reports that HSCT is effective as a treatment even for neurological symptoms in PNP deficiency.
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| 3. |
- Brodszki, Nicholas, et al.
(författare)
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Novel treatment of severe combined immunodeficiency utilizing ex-vivo T-cell depleted haploidentical hematopoietic stem cell transplantation and CD45RA+ depleted donor lymphocyte infusions.
- 2016
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment available for severe combined immunodeficiency (SCID); although, there is a high incidence of severe infections and an increased risk of graft-versus host-disease (GvHD) with HSCT. Early intervention is a crucial prognostic factor and a HLA-haploidentical parental donor is often available. Haploidentical HSCT protocols utilizing extensively ex vivo T-cell depleted grafts (CliniMACs system) have proven efficient in preventing GvHD, but cause a delay in early T-cell recovery that increases the risk of viral infections. Here, we present a novel approach for treating SCID that combines selective depletion of GvHD-inducing alpha/beta (α/β) T-cells from the haploidentical HSCT graft with a subsequent donor lymphocyte infusion (DLI) enriched for CD45RO+ memory T-cells.
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| 4. |
- Brodszki, Nicholas
(författare)
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Primary immunodeficiency in southern Sweden. Strategies for diagnosis and clinical management
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim of this PhD project was to gain insight into the incidence of primary immunodeficiency (PID) in southern Sweden and to optimize diagnostic and treatment measures for these patients. We estimated the occurrence rate of PID in the pediatric population of southern Sweden during a period of 4 years and described the demographic, clinical and immunological characteristics of the identified cases. The occurrence rate of PID was about four new cases per year in this population. Several different PID diagnoses were found, and the application of specified criteria to identify PID patients was useful. In children who are prone to infection, the use of a predefined set of immunological laboratory analyses at their first examination was beneficial for early identification of patients with primary immunodeficiency. Complement C2 deficiency (C2D) is associated with immunological diseases and increased susceptibility to invasive infections caused by encapsulated bacteria such as Neisseria (N.) meningitidis. We evaluated the immunogenicity of vaccination against N. meningitidis in C2D patients and healthy controls who received a tetravalent meningococcal vaccine. Response was measured by determining serum bactericidal antibody (SBA) titers against the four meningococcal serogroups A, C, Y and W included in the vaccine. We also investigated other immunological factors that could influence the vaccine responses. In general, vaccination against meningococci gave rise to antibody responses in the C2D patients that equal those of healthy controls. The response rate was lower to serogroup A and among C2D patients with history of invasive infections. The presence of G2M*n/G2M*n genotype was associated with higher SBA titers after immunization. None of the other tested immunological factors influenced the vaccination responses. We described the first Swedish patient with purine nucleoside phosphorylase (PNP) deficiency with novel mutations in the PNP gene. We presented also the results of the hematopoietic stem cell transplantation (HSCT) and evaluated the impact of HSCT on the neurological symptoms. We could conclude that HSCT is curative for the immunological defect caused by PNP deficiency and our case strengthens earlier reports that HSCT is effective as a treatment even for neurological symptoms in PNP deficiency. We presented a novel approach of treating SCID by successfully combining a haploidentical HSCT with a subsequent donor lymphocyte infusion (DLI). No acute or chronic graft-versus-host disease (GvHD) was observed after any of the procedures. The HSCT graft was selectively depleted of potentially GvHD-inducing α/β T-cells while the DLI graft was enriched for memory T-cells for enhanced anti-viral immunity. HSCT engraftment was rapid with complete donor chimerism and after DLI the T-cell levels normalized and all infections were cleared.
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| 5. |
- Mori, Michiko, et al.
(författare)
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Pulmonary and pleural lymphatic endothelial cells from pediatric, but not adult, patients with Gorham-Stout disease and generalized lymphatic anomaly, show a high proliferation rate
- 2016
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Gorham-Stout disease (OMIM 123880) and generalized lymphatic anomaly are two rare disorders of lymphendothelial growth in which thoracic involvement with chylothorax is a feared complication. Currently it is believed that both disorders are prenatal malformations that progress slowly after birth. Several pharmaceuticals with antiproliferative properties, including interferon-α-2b, rapamycin and propranolol, have however been shown to affect the disease course in some patients. Deeper knowledge of the growth characteristics of these malformations are therefore needed to guide the clinical approach. Methods: Lymphatic vessels in lung and pleural tissue from both children and adult patients with generalized lymphatic anomaly or Gorham-Stout disease were studied using an immunohistochemical approach, targeting lymphendothelial markers (D2-40/Prox-1) and a proliferation marker (Ki-67). Results: We found significant proliferation and growth in these lesions in pediatric patients but not in adults. Furthermore, the data may suggest that the disease process is at least partly reversible. Conclusions: These malformations of the lymphatic system proliferate at a significant rate long after birth, which could suggest that the clinical approach for children should be different from adults.
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