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Fc gamma-receptor polymorphisms associated with clinical symptoms in patients with immunoglobulin G subclass deficiency
Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Ryhov Cty Hosp, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.ORCID iD: 0000-0001-5719-5601
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2018 (English)In: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 50, no 11-12, p. 853-858Article in journal (Refereed) Published
Abstract [en]

Background: Immunoglobulin G subclass deficiencies (IgGsd) are associated with recurrent respiratory tract infections. Immunoglobulin substitution therapy may be needed to prevent chronic lung tissue damage but tools for identifying the patients that will benefit from this treatment are still insufficient. Some Fc gamma R polymorphisms seem to predispose for an increased risk for infections. In this study we wanted to evaluate if the Fc gamma R-profile differs between individuals with IgGsd and a control population. Methods: Single nucleotide polymorphisms (SNPs) of Fc gamma RIIa, Fc gamma RIIIa and Fc gamma RIIc in 36 IgGsd patients and 192 controls with similar sex and geographical distribution were analyzed by TaqMan allelic discrimination assay or Sanger sequencing. Results: In the IgGsd-group, homozygous frequency for Fc gamma RIIa-R/R131 (low-binding capacity isoform) was higher (p = .03) as well as for non-classical Fc gamma RIIc-ORF (p = .03) and classical Fc gamma RIIc-ORF tended (p = .07) to be more common compared to the controls. There was no difference between the groups regarding Fc gamma RIIIa. Conclusion: The gene for classical Fc gamma RIIc-ORF tended to be more frequent in individuals with immunoglobulin G subclass deficiency and the genes for non-classical Fc gamma RIIc-ORF as well as low-binding capacity receptor Fc gamma RIIa-R/R131 were more frequent. Further studies on the Fc gamma R polymorphisms may pave way for identifying individuals that will benefit from immunoglobulin substitution.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD , 2018. Vol. 50, no 11-12, p. 853-858
Keywords [en]
Fc gamma-receptor; Polymorphism; Respiratory tract infection; Immunoglobulin G subclass deficiency
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:liu:diva-154728DOI: 10.1080/23744235.2018.1510183ISI: 000457473500009PubMedID: 30298768OAI: oai:DiVA.org:liu-154728DiVA, id: diva2:1292256
Note

Funding Agencies|FORSS [forss-654371]; Futurum [futurum-709431]

Available from: 2019-02-27 Created: 2019-02-27 Last updated: 2023-08-31
In thesis
1. Clinical and immunological aspects of IgG subclass deficiency: Predictors for the need of immunoglobulin replacement therapy
Open this publication in new window or tab >>Clinical and immunological aspects of IgG subclass deficiency: Predictors for the need of immunoglobulin replacement therapy
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Predominantly antibody deficiencies (PAD) are inborn errors of immunity, and associate with increased susceptibility to infections. Life-long immunoglobulin replacement therapy (IgRT) is introduced based on Ig-levels and the frequencies and severity of infections. The subgroup of PAD with immunoglobulin G subclass deficiency (IgGsd) is often less severe and the need of IgRT in these patients is unclear. Often many years pass before IgGsd is diagnosed, and repeated respiratory tract infections risk to confer lung tissue damage. The Swedish standard regimen in IgGsd is IgRT during 18 months followed by a period of discontinuation in order to evaluate the effect and restart it, if infections reoccur. It is a challenge to identify the subgroup of IgGsd-individuals in need of life-long treatment, and early reliable markers are warranted. 

Aim: The aim of this thesis was to identify clinical and laboratory factors predicting the need of long-term IgRT in IgGsd and evaluate its effects on immunological functions. Results: In paper I, the established clinical warning sign that is used to identify individuals with PAD in need of IgRT, was evaluated regarding the accuracy to identify IgGsd in a primary care register with data from 350,000 visits due to respiratory tract infections. The predictive value was low and according to medical records, a primary immunodeficiency was rarely suspected. In paper II, a lower frequency of homozygosity for the high affinity IgG receptor FcγRIIa H/H131 were found in IgGsd compared to controls. The finding supports the hypothesis that FcγR-polymorphisms may be of importance for susceptibility to infections in IgGsd and may have impact on the need of IgRT. In paper III, patient reported outcome showed that severe fatigue and low health related quality of life associated with the need of life-long IgRT. Systemic inflammation is known to associate with fatigue and in paper III and IV extensive immunophenotyping was performed when on and off IgRT. IgGsd patients were characterized by dysregulated plasma protein profiles enriched for factors associated with interleukin 10 signaling that were unaffected by IgRT. Among circulating immune cells, decreased proportions of activated B- and T cell subsets, as well as regulatory T cells, were found and partly restored during IgRT. Individuals needing life-long IgRT had a lower prevalence of protective pneumococcal specific IgG against 21 tested capsular serotypes. Co-morbidity with autoimmunity, atopy, lung disease and other factors such as higher age and occupation also associated to the need of IgRT. 

Conclusion: IgGsd patients were characterized by increased systemic inflammation, which was unaffected by IgRT. Decreased activation of lymphocyte subsets was partly restored during IgRT. Severe fatigue, protective IgG levels against a low number of pneumococcal serotypes, especially in conjunction with comorbidities were associated with the need for IgRT. Overall, no factor alone could predict the need of life-long IgRT.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2022. p. 64
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1811
Keywords
Immunoglobulin G subclass deficiency, inflammation, lymphocytes, fatigue, co-morbidity, immunoglobulin G replacement therapy
National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-189644 (URN)10.3384/9789179293055 (DOI)978-91-7929-304-8 (ISBN)978-91-7929-305-5 (ISBN)
Public defence
2022-11-25, Originalet, Qulturum, Länssjukhuset Ryhov, Jönköping, 09:00
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Available from: 2022-10-31 Created: 2022-10-31 Last updated: 2022-11-03Bibliographically approved

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Wågström, PerYamada, NaomiDahle, CharlotteNilsdotter-Augustinsson, ÅsaSöderkvist, PeterBjörkander, Jan Fredrik
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