Polymorphism of FCGR2A, FCGR2C, and FCGR3B Genes in the Pathogenesis of Sarcoidosis

Abstract

We have previously presented evidence that the polymorphism of the FCGR3A gene, encoding the receptor for Fc fragment of immunoglobulin G IIIa (FcγRIIIa) plays a role in the enhancement of circulating immune complexes (CIs) with the occurrence of Mycobacterium tuberculosis heat shock proteins in patients with sarcoidosis (SA). The immunocomplexemia might be caused by decreased affinity of CIs to Fcγ receptors, with the subsequently decreased receptor clearance by immune cells. In the present study we examined whether the polymorphisms of other related genes (FCGR2A, FCGR2C, FCGR3B) encoding other activatory Fcγ receptors, could have a similar effect. To this end, we genotyped 124 patients with sarcoidosis and 148 healthy volunteers using polymerase chain reaction with sequence-specific primers. We revealed a significant decrease in the percentage of the FCGR2A and FCGR2C variants that ensure effective CIs clearance, with a concomitant increase of less functional variants of these genes in Stages I/II, compared with Stages III/IV of SA. There was no aberration in FCGR3B allele/genotype frequencies. We conclude that the FCGR2A and FCGR2C polymorphisms may also contribute to immunocomplexemia present in SA. The assessment of FCGR genes could become a tool in presaging a clinical course of sarcoidosis and in its personalized therapy.

Copy number variation of FCGR genes in etiopathogenesis of sarcoidosis

“…This is in agreement with previously shown elevated presence of both FcγR class II and III receptors on monocytes in peripheral blood of our patients with sarcoidosis [10]. Moreover, in our previous study we have reported an increase in frequency of functional 57Q allele and 57XQ genotype of FCGR2C gene in Stage III and IV of SA [12]. In contrast to a 57X allele, creating a stop codon, presence of 57Q allele of FCGR2C results in production of a full-length, functional FcγRIIc receptor on a surface of immune cells.…”

“…Additionally, since FcγRIIIb is bound to a cell membrane only with a glycosylphosphatidylinositol anchor, it needs to colocalise with and signal through other receptors, such as FcγRIIa, in order to trigger neutrophils’ phagocytosis, oxidative burst and formation of neutrophil extracellular traps in tissues, a proinflammatory process that is linked to autoimmunity [35]. In our previous study, we have shown increased frequency of 131HH genotype of FCGR2A gene, encoding FcγRIIa, in more advanced stages of SA versus initial Stages I/II [12]. The possession of 131HH genotype results in higher affinity of FcγRIIa receptor to immune complexes and initiation of augmented (auto)immune response.…”

“…It could point to lowered affinity of FcγRs to ICs due to polymorphism of FCGR genes, encoding Fcγ receptors from classes II and III ( FCGR2A , FCGR2B , FCGR2C , FCGR3A , FCGR3B ), and/or aberration in their copy number (CN), which has been revealed in many other autoimmune disorders, but not yet in SA. Therefore, we have analyzed polymorphism of these genes in our SA patients and revealed that, in contrast to polymorphism of FCGR2B and FCGR3B , polymorphism of FCGR2A , FCGR2C and FCGR3A may contribute to immunocomplexemia present in sarcoidosis [11,12]. Moreover, since an aberrated number of copies (CN ≠ 2) of FCGR genes would lead to disruption in the presence of FcγRs on immune cells, causing up- or down-regulation of an (auto)immune response, in the current study we performed the first in the world analysis of copy number variation (CNV) of FCGR2A , FCGR2B , FCGR2C , FCGR3A and FCGR3B genes in an ethnically homogenous, Caucasian group of patients with sarcoidosis and healthy controls.…”

The association between osteopontin gene polymorphisms, osteopontin expression and sarcoidosis

“…Several studies have described d a connection between the presence of Mycobacterium tuberculosis heat-shock proteins in sarcoidosis patients and polymorphisms of genes encoding for FC receptor γ. This suggests that reduced clearance of TB immune complex may be relevant in the pathogenesis of sarcoidosis [ 15 ]. Familial clusters have been described, but are relatively uncommon.…”

Assessing severity of cardiac sarcoid: Is SUV the answer?

“…Another genetic polymorphism, FCGR2A and FCGR2C, has been identified as a potential tool in predicting clinical course of sarcoidosis. 10…”