Fibrinogen-like protein 2, also known as FGL2, is a protein which in humans is encoded by the FGL2 gene. [5] [6]
Fibrinogen-like protein 2, also known as FGL2, is a protein which in humans is encoded by the FGL2 gene. [5] [6]
FGL2 is a 439 amino acid secreted protein that is similar to the β- and γ-chains of fibrinogen. The carboxyl-terminus of the encoded protein consists of the fibrinogen-related domains (FRED). The encoded protein forms a tetrameric complex which is stabilized by interchain disulfide bonds. [5]
This protein may play a role in physiologic functions at mucosal sites.
FGL2 is a protein that exhibits pleiotropic effects within the body and is an important immune regulator of both innate and adaptive responses. [7] The protein exists as both a Type II transmembrane protein (with the carboxy terminus on the extracellular side of the plasma membrane) found on the surface of macrophages and endothelial cells and can be constitutively secreted by both CD4+ and CD8+ T cells. [7]
Membrane bound FGL2 (mFGL2) exhibits a prothrombinase activity, resulting in fibrin deposition, vascular thrombosis and tissue inflammation within an affected tissue, largely contributing to the innate arm of immunity. [8] Through mFGL2’s actions of promoting vascular thrombosis and tissue inflammation, it has been implicated in the pathogenesis of viral-induced fulminant hepatitis in acute hepatitis B infections. [9] Hepatocellular necrosis ensues rapidly, due to the HBV nucleocapsid protein’s ability to markedly upregulate expression of the mFGL2 prothrombinase, leading to fibrin deposition within the vasculature networks that supply blood to the liver. [9]
In addition to its constitutive secretion by CD4+ and CD8+ T cells, the secreted form of FGL2 (sFGL2) can be inducibly secreted by Foxp3+ CD4+ CD25+ T regulatory cells (Tregs). Such Treg cells play a vital role in dampening the immune response after the clearance of an infection to prevent sterile inflammation. These cells also play a fundamental role in maintaining self tolerance by suppressing the activation and expansion of self-reactive lymphocytes that may instigate autoimmunity.[ citation needed ]9 Through their roles in immune homeostasis, it has been shown that depletion of the Treg cell population in murine models for disease lead to enhanced immune responses to a variety of infectious agents including hepatitis C virus (HCV).[ citation needed ]10 Additionally, patients with a chronic HCV infection were shown to have higher counts of Treg cells in peripheral blood when compared with successfully treated or healthy controls.[ citation needed ]11
Secreted FGL2 (sFGL2) plays a role as a negative regulator of the Immune response. sFGL2 inhibits the adaptive immune response. Knockout mice for FGL2 have T cells that are hyperproliferative. [10] sFGL2 is capable of inhibiting the proliferation of T cells stimulated by alloantigens and this inhibition is alleviated by the addition of a monoclonal antibody against sFGL2’s fibrinogen-like domain (FRED).[ citation needed ]12 When the supernatants of these T cell cultures are analyzed, they showed a predominant Th2 type polarization with upregulated levels of expression of interleukin-4 (IL-4) and Interleukin-10 (IL-10).[ citation needed ]12 There are also downregulated levels of Th1-type cytokines such as interleukin-2 (IL-2) and interferon γ (IFN-γ). [10] This shows that sFGL2 largely inhibits the Th1 type response needed to activate cytotoxic lymphocytes to clear HCV infections. Additionally, sFGL2 can inhibit the maturation of immature dendritic cells (DCs) by preventing NF-κB translocation to the nucleus and subsequent expression of the co-stimulatory molecule CD80 and major histocompatibility complex II (MHC II). [10] Therefore, sFGL2 may contribute to the negative regulatory activity exhibited by Treg cells.
sFGL2 works to repress immune response through its FRED Domain. The immunosuppressive activity of sFGL2 has been localized to the C-terminal region containing the FRED domain. sFGL2’s FRED domain shares significant homology to the fibrinogen related domains of potent immunoregulatory molecules like cytotaxin and tenascin.[ citation needed ]12 This works to repress immune responses by binding to the inhibitory FC receptor, FCγRIIB. Furthermore, HCV’s core protein has been found to increase the levels of expression of sFGL2 and cause virus-specific CD4+ T lymphocytes to skew largely toward a Th2 lineage, allowing for the establishment of a chronic infection.[ citation needed ]13
Human Fibrinogen-like protein 2 may be useful as a biomarker for responsiveness to antiviral therapy. [11]
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.
Granzyme A is a tryptase and is one of the five granzymes encoded in the human genome. In humans, GzmA is encoded by the GZMA gene in proximity to the GZMK gene on chromosome 5. This enzyme is present in cytotoxic T lymphocyte (CTL) granules.
HLA class II histocompatibility antigen, DR alpha chain is a protein that in humans is encoded by the HLA-DRA gene. HLA-DRA encodes the alpha subunit of HLA-DR. Unlike the alpha chains of other Human MHC class II molecules, the alpha subunit is practically invariable. However it can pair with, in any individual, the beta chain from 3 different DR beta loci, DRB1, and two of any DRB3, DRB4, or DRB5 alleles. Thus there is the potential that any given individual can form 4 different HLA-DR isoforms.
Complement receptor type 2 (CR2), also known as complement C3d receptor, Epstein-Barr virus receptor, and CD21, is a protein that in humans is encoded by the CR2 gene.
Interleukin-26 (IL-26) is a protein that in humans is encoded by the IL26 gene.
Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.
Major histocompatibility complex, class II, DR beta 4, also known as HLA-DRB4, is a human gene.
CD83 is a human protein encoded by the CD83 gene.
CD69 is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentiation as well as lymphocyte retention in lymphoid organs.
CD81 molecule, also known as CD81, is a protein which in humans is encoded by the CD81 gene. It is also known as 26 kDa cell surface protein, TAPA-1, and Tetraspanin-28 (Tspan-28).
HLA class II histocompatibility antigen, DM beta chain is a protein that in humans is encoded by the HLA-DMB gene.
Semaphorin-4D (SEMA4D) also known as Cluster of Differentiation 100 (CD100), is a protein of the semaphorin family that in humans is encoded by the SEMA4D gene.
HLA class II histocompatibility antigen, DO alpha chain is a protein that in humans is encoded by the HLA-DOA gene.
SLAM family member 6 is a protein that in humans is encoded by the SLAMF6 gene.
CD6 is a human protein encoded by the CD6 gene.
Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.
Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.
HLA class II histocompatibility antigen, DX beta chain is a protein that in humans is encoded by the HLA-DQB2 gene.
T-cell surface glycoprotein CD8 alpha chain, is a protein encoded by CD8A gene.
CD28 family receptors are a group of regulatory cell surface receptors expressed on immune cells. The CD28 family in turn is a subgroup of the immunoglobulin superfamily.
[12] Chan CW et al. "Soluble fibrinogen-like protein 2/fibroleukin exhibits immunosuppressive properties: suppressing T cell proliferation and inhibiting maturation of bone marrow-derived dendritic cells." J Immunol. 2003 Apr 15;170(8):4036-44.