Newborn screening for severe primary immunodeficiencies
Author: Borte, Stephan
Date: 2014-09-24
Location: Huddinge Hospital, Institutionen för laboratoriemedicin, H5-ÖVR, Lokal 4Z
Time: 10.00
Department: Inst för laboratoriemedicin / Dept of Laboratory Medicine
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Thesis (1.466Mb)
Abstract
Primary immunodeficiencies (PID) are congenital disorders of immune competence, which are
mainly characterized by a pathological susceptibility to infection. This is often accompanied by
severe recurrent infections with drug-resistant, long progressions. In addition, there are associated
immune regulation disorders, which may manifest themselves in granuloma formation, autoimmunity,
recurrent fever, eczema, lymphoproliferation and chronic intestinal inflammation.
More than 240 disease entities have been defined so far as PID, and just as extensive is the
spectrum of clinical severity. While the most common congenital immunodeficiencies, such as
selective IgA deficiency or C2 complement deficiency, have a mild phenotype which often
remains undetected, severe PID are characterized by significant mortality in the first years of life,
as well as a serious morbidity with irreversible organ damage. This applies in particular to PID
that are defined by the absence or functional anergy of T-lymphocytes (severe combined
immunodeficiency; SCID) or B-lymphocytes (e.g. X-linked agammaglobulinemia; XLA).
Patients with such severe congenital immunodeficiencies appear to be in perfect health at birth,
yet show initial manifestations of SCID between the 14th day and the 4th month following birth;
in patients with XLA usually between the 8th and 16th month after birth.
Albeit increasingly becoming appreciated as a relevant health problem, there is a lack of diagnostic procedures and screening profiles that would allow earliest possible diagnosis of patients with severe PID on a population scale. As a superior prognosis could be given upon prompt diagnosis and immediate adequate treatment, one strategy to improve the outcome of severe PID shall be to test newborns for the presence of T and B cells. With the aim to develop a simple and reliable test for newborn screening using the established dried blood sampling system (Guthrie cards), a multiplex real-time quantitative qPCR assay for the quantitation of T cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) as surrogate markers of T and B cell development was designed and evaluated (publication I). This assay was further extended to allow detection of newborns with an inversion of the UNC13D gene, causing a severe PID characterized as familial hemophagocytic lymphohistiocytosis (publication III). Furthermore, the feasibility to identify several other severe PID, characterized by a functional defect of T- and B-cell interation (combined immunodeficiency diseases), was assessed using IgA-protein detection in neonatal Guthrie cards. However, this assay provided evidence of a maternal transfer mechanism for IgA, thereby preventing the use of this assay as a screening tool for severe PID (publication II). Finally, the TREC-KREC newborn screening assay was further improved in terms of assay performance and evaluated in retrospective cohorts of patients with the DiGeorge syndrome, or Down syndrome (publications IV and V). In addition, novel second-tier assays for comfirmation of the 22q11 microdeletion or the chromosome 21 triplication have been designed and succesfully tested with neonatal samples.
In summary, new assays and concepts for newborn screening of severe primary immunodeficeincies were designed and benchmarked in retrospective and prospective neonatal dried blood spot samples, thereby underlining the potential of this preventive health care strategy.
Albeit increasingly becoming appreciated as a relevant health problem, there is a lack of diagnostic procedures and screening profiles that would allow earliest possible diagnosis of patients with severe PID on a population scale. As a superior prognosis could be given upon prompt diagnosis and immediate adequate treatment, one strategy to improve the outcome of severe PID shall be to test newborns for the presence of T and B cells. With the aim to develop a simple and reliable test for newborn screening using the established dried blood sampling system (Guthrie cards), a multiplex real-time quantitative qPCR assay for the quantitation of T cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) as surrogate markers of T and B cell development was designed and evaluated (publication I). This assay was further extended to allow detection of newborns with an inversion of the UNC13D gene, causing a severe PID characterized as familial hemophagocytic lymphohistiocytosis (publication III). Furthermore, the feasibility to identify several other severe PID, characterized by a functional defect of T- and B-cell interation (combined immunodeficiency diseases), was assessed using IgA-protein detection in neonatal Guthrie cards. However, this assay provided evidence of a maternal transfer mechanism for IgA, thereby preventing the use of this assay as a screening tool for severe PID (publication II). Finally, the TREC-KREC newborn screening assay was further improved in terms of assay performance and evaluated in retrospective cohorts of patients with the DiGeorge syndrome, or Down syndrome (publications IV and V). In addition, novel second-tier assays for comfirmation of the 22q11 microdeletion or the chromosome 21 triplication have been designed and succesfully tested with neonatal samples.
In summary, new assays and concepts for newborn screening of severe primary immunodeficeincies were designed and benchmarked in retrospective and prospective neonatal dried blood spot samples, thereby underlining the potential of this preventive health care strategy.
List of papers:
I. Borte S, von Döbeln U, Fasth A, Wang N, Janzi M, Winiarski J, Sack U, Pan-Hammarström Q, Borte M, Hammarström L: Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR. Blood. 2012; 119 : 2552-2555.
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II. Borte S, Janzi M, Pan-Hammarström Q, von Döbeln U, Nordvall L, Winiarski J, Fasth A, Hammarström L: Placental transfer of maternallyderived IgA precludes the use of guthrie card eluates as a screening tool for primary immunodeficiency diseases. PLoS One. 2012; 7 : e43419.
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View record in Web of Science®
III. Borte S, Meeths M, Liebscher I, Krist K, Nordenskjöld M, Hammarström L, von Döbeln U, Henter JI, Bryceson YT: Combined newborn screening for familial hemophagocytic lymphohistiocytosis and severe T- and B-cell immunodeficiencies. J Allergy Clin Immunol. 2014; 134 : 226-228
Fulltext (DOI)
Pubmed
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IV. Verstegen RH, Borte S, Bok LA, van Zwieten PH, von Döbeln U, Hammarström L, de Vries E: Impact of Down syndrome on the performance of neonatal screening assays for severe primary immunodeficiency diseases. J Allergy Clin Immunol. 2014; 133 : 1208- 1211.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Lingman Framme J, Borte S, von Döbeln U, Hammarström L, Oskarsdóttir S: Retrospective analysis of TREC based newborn screening results and clinical phenotypes in infants with the 22q11 deletion syndrome. J Clin Immunol. 2014; 34 : 514-519.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Borte S, von Döbeln U, Fasth A, Wang N, Janzi M, Winiarski J, Sack U, Pan-Hammarström Q, Borte M, Hammarström L: Neonatal screening for severe primary immunodeficiency diseases using high-throughput triplex real-time PCR. Blood. 2012; 119 : 2552-2555.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Borte S, Janzi M, Pan-Hammarström Q, von Döbeln U, Nordvall L, Winiarski J, Fasth A, Hammarström L: Placental transfer of maternallyderived IgA precludes the use of guthrie card eluates as a screening tool for primary immunodeficiency diseases. PLoS One. 2012; 7 : e43419.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Borte S, Meeths M, Liebscher I, Krist K, Nordenskjöld M, Hammarström L, von Döbeln U, Henter JI, Bryceson YT: Combined newborn screening for familial hemophagocytic lymphohistiocytosis and severe T- and B-cell immunodeficiencies. J Allergy Clin Immunol. 2014; 134 : 226-228
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Verstegen RH, Borte S, Bok LA, van Zwieten PH, von Döbeln U, Hammarström L, de Vries E: Impact of Down syndrome on the performance of neonatal screening assays for severe primary immunodeficiency diseases. J Allergy Clin Immunol. 2014; 133 : 1208- 1211.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Lingman Framme J, Borte S, von Döbeln U, Hammarström L, Oskarsdóttir S: Retrospective analysis of TREC based newborn screening results and clinical phenotypes in infants with the 22q11 deletion syndrome. J Clin Immunol. 2014; 34 : 514-519.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Hammarström, Lennart
Issue date: 2014-09-04
Rights:
Publication year: 2014
ISBN: 978-91-7549-659-7
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