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Fc receptors and immunoglobulins in polyarthritis: A matter of function, supply and demand?
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Fc receptors (FcR) and immunoglobulins (Ig) play important roles in the defence against pathogens. However, altered interactions of these may promote chronic inflammation in rheumatic diseases. An excess of Igs forming immune complexes (IC) could lead to continuous FcR activation and spreading of autoimmune inflammation to other tissues.This work focuses on the evaluation of the FcR status and function in the two most common polyarthritides - psoriatic arthritis (PsA) and rheumatoid arthritis (RA) – in relation to various Igs, joint and skin disease activity, and effect of anti-rheumatic treatment (determined by the EULAR response criteria for RA). Monocyte subpopulations (defined by surface CD14 and CD16 expressions) in patients and HC were also characterised, since different monocyte subsets may have opposing functions in inflammatory conditions. In addition, the effect and safety of long-term B-cell suppression in advanced RA was studied.

In PsA, elevated serum levels of IgG1, 2, and 3 were noted while the early naïve RA patients - besides being positive for autoantibodies like IgMRF, IgARF, IgGRF, and ACPA IgG - were distinguished by high levels of IgG1 and IgG3. Monocytes of PsA and RA patients were heavily loaded with IgG and expressed more CD64 (i.e. the high affinity FcγR) than HC. An increase in CD64 turnover was specific for early RA, while a higher CD16a (i.e. a low affinity FcγR) turnover was seen in both RA and PsA compared with HC. The FcγR function was impaired in both polyarthritides compared to HC, but the RA monocytes were more affected of this than the PsA monocytes. RA non-responders had a much lower capacity of IC binding compared with RA good responders. Alterations of the FcR status and function reflected joint disease activity markers in both polyarthritides but not the skin disease activity in PsA. I therefore conclude that the observed FcR statuses in both diseases were specific for joint inflammation. In addition, RA patients with high levels and the occurrence of several simultaneously appearing RF isotypes presented a minor FcγR function, while patients experiencing a good treatment effect were more likely to show low levels of Igs. This suggests that RFs/IC in excess could be important promotors of the ongoing inflammation in RA. However, for ACPA IgG no associations with the rheumatoid monocytic FcR status/function were noted. CD16negative classical monocytes were elevated in early naïve RA, especially in the non-responders - while PsA patients showed an increase in CD16low expressing cells compared to HC. These observations indicate that different monocyte subpopulations could be important in the two polyarthritides. In a cohort of RA patients with advanced disease, long-term B-cell suppression resulted in conversion to RF negativity which indicated a good treatment response but not an increased risk of infection. 

FcRs and Igs are important players that promote chronicity of inflammation in polyarthritis, especially in RA. An impaired FcγR function following an excess of Igs/IC reflects this state of the immune system. This work has identified an increased monocytic CD64 turnover as a RA specific feature. Future treatment options in RA might include supporting/normalizing the FcγR function. Today suppressing B-cell activity is an effective and relatively safe way to tackle the problem from the opposite side.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 64 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1250
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-301173ISBN: 978-91-554-9667-8OAI: oai:DiVA.org:uu-301173DiVA: diva2:953851
Public defence
2016-10-06, Gunnesalen, Psykiatrins Hus, ING 10, Akademiska sjukhuset, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2016-09-15 Created: 2016-08-18 Last updated: 2016-09-22
List of papers
1. Rheumatoid factor isotypes reflect the monocyte Fcγ receptor function and treatment outcome in early naïve rheumatoid arthritis
Open this publication in new window or tab >>Rheumatoid factor isotypes reflect the monocyte Fcγ receptor function and treatment outcome in early naïve rheumatoid arthritis
(English)Manuscript (preprint) (Other academic)
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-301170 (URN)
Available from: 2016-08-18 Created: 2016-08-18 Last updated: 2016-08-26Bibliographically approved
2. B-cell depletion in rheumatoid arthritis: conversion to RF negativity indicates a good treatment response but not an increased risk of infection
Open this publication in new window or tab >>B-cell depletion in rheumatoid arthritis: conversion to RF negativity indicates a good treatment response but not an increased risk of infection
(English)Manuscript (preprint) (Other academic)
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-301172 (URN)
Available from: 2016-08-18 Created: 2016-08-18 Last updated: 2016-08-26Bibliographically approved
3. Up-regulation of CD64-expressing monocytes with impaired Fc gamma R function reflects disease activity in polyarticular psoriatic arthritis
Open this publication in new window or tab >>Up-regulation of CD64-expressing monocytes with impaired Fc gamma R function reflects disease activity in polyarticular psoriatic arthritis
2015 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 44, no 6, 464-473 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: The aim of this study was to assess monocyte Fc receptor (FcR) status and function in patients with active psoriatic arthritis (PsA) in relation to healthy controls (HC) and to disease activity.Method:The study population comprised 23 patients with active polyarticular PsA and 33 age- and gender-matched HC. Immunoglobulin (Ig) levels, inflammatory laboratory parameters, patient-reported outcomes of joint disease activity, skin scoring (Psoriasis Area and Severity Index, PASI), and joint status were determined in the patients. Monocytes were analysed for the expression of FcRs for IgG (FcR) class I (CD64), IIa (CD32a), IIb (CD32b), and III (CD16), the FcR for IgA (FcR) (CD89), and surface-bound IgG. The monocytic FcR function was assessed by evaluating IgG immune complex (IC) binding and tumour necrosis factor (TNF)- production following IgG-IC stimulation. The monocytes were further subdivided and analysed according to their CD14 and CD16 expression.Results:The PsA patients presented elevated serum levels of IgG1, 2, and 3 and increased numbers of CD64(+) monocytes. Furthermore, the PsA monocytes exhibited increased cell-bound IgG, and the FcR function was affected in terms of reduced IgG-IC-mediated TNF- release. These findings correlated significantly with different markers of joint disease activity. PsA was also accompanied by an increase in the CD16 low-expressing monocyte subset.Conclusions:An intensified humoral immune response affects monocytes and their FcR status in active polyarticular PsA. The up-regulated CD64(+) monocytes seem to be have an important role in psoriatic joint inflammation. These cells may prove to be a useful target in future PsA therapeutic interventions.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-274343 (URN)10.3109/03009742.2015.1020864 (DOI)000364826400006 ()26084203 (PubMedID)
Funder
Swedish Research Council
Available from: 2016-01-21 Created: 2016-01-21 Last updated: 2016-08-26Bibliographically approved
4. Elevated Membrane and Soluble CD64: A Novel Marker Reflecting Altered Fc gamma R Function and Disease in Early Rheumatoid Arthritis That Can Be Regulated by Anti-Rheumatic Treatment
Open this publication in new window or tab >>Elevated Membrane and Soluble CD64: A Novel Marker Reflecting Altered Fc gamma R Function and Disease in Early Rheumatoid Arthritis That Can Be Regulated by Anti-Rheumatic Treatment
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, e0137474Article in journal (Refereed) Published
Abstract [en]

Objectives Fc receptors (FcR) interacting with immune complexes (ICs) is a central event in the immune pathogenesis of rheumatoid arthritis (RA). Here we asked if a specific FcR is linked to RA pathogenesis and if FcR activities relate to disease and treatment outcome in early RA. Material and Methods Twenty autoantibody-positive RA patients and 33 HC were included. The patients were evaluated before and after treatment with methotrexate and prednisolone. At follow-up, the EULAR response criteria were applied to determine the individual treatment outcomes. Serum immunoglobulin levels were measured and the expression of FcR for IgG (Fc gamma R) and IgA (Fc alpha R) on peripheral blood monocytes were determined by flow cytometry. The monocytic Fc gamma R function was evaluated by human IgG1 and IgG3 IC-binding and TNF alpha stimulated release. Plasma levels of soluble FcRs (sFcRs) were determined with ELISA. Results The IgG1 and IgG3 levels were elevated in the RA sera. The RA monocytes expressed more CD64 and cell surface-bound IgG than HC monocytes, and showed an impaired Fc gamma R function as reflected by changes in IC-binding and decreased IC-stimulated TNF alpha secretion. These findings correlated significantly with different disease activity markers. Furthermore, sFcRs were elevated in the patient plasma, and sCD64 was specific for RA (compared with a reference group of patients with active psoriatic arthritis). Following treatment, immunoglobulins and sFcR levels were reduced, whereas membrane CD64 was only decreased in patients with good response to treatment. Conclusions Early RA patients display increased membrane and soluble CD64 and an impaired Fc gamma R function correlating with joint disease activity. Beneficial responses of anti-rheumatic treatment in patients reduce CD64. These data suggest sCD64 as an important objective biomarker in RA.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-265908 (URN)10.1371/journal.pone.0137474 (DOI)000361800700021 ()26406605 (PubMedID)
Available from: 2015-11-04 Created: 2015-11-04 Last updated: 2016-08-26Bibliographically approved

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