Macrophage colony-stimulating factor 1 receptor (CSF1R) is a member of the type III subfamily of receptor tyrosine kinases that also includes receptors for SCF and PDGF. These receptors each contain five immunoglobulin-like domains in their extracellular domain (ECD) and a split kinase domain in their intracellular region. CSF1R is expressed primarily on cells of the monocyte/macrophage lineage, dendritic cells, stem cells and in the developing placenta. CSF1 and its receptor (CSF1R, product of c-fms proto-oncogene) were initially implicated as essential for normal monocyte development as well as for trophoblastic implantation. It plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption, and is required for normal bone and tooth development. It is required for normal male and female fertility, and for normal development of milk ducts and acinar structures in the mammary gland during pregnancy. Aberrant expression of CSF1 or CSF1R may play a role in inflammatory diseases, such as rheumatoid arthritis, glomerulonephritis, atherosclerosis, and allograft rejection.
Cytotoxic Tlymphocyte 4(CTLA-4,CD152), is a type I transmembrane T cell inhibitory molecule that is a member of the Ig superfamily.CD28 and CTLA-4, together with their ligands, B7-1 and B7-2, constitute one of the dominant costimulatory pathways that regulate T and B cell responses. CD28 and CTLA-4 are structurally homologous molecules that are members of the immunoglobulin (Ig) gene superfamily. CTLA4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. Intracellular CTLA4 is also found in regulatory T Cells and may play an important role in their functions. Tcell activation through the Tcell receptor and CD28 leads to increased expression of CTLA4.
Receptors for the Fc region of immunoglobin G (FcγR) are divided into three classes and FcγRIII is a multifunctional, low/intermediate affinity receptor. In humans, FcγRIII is expressed as two distinct forms (FcγRIIIA and FcγRIIIB) that are encoded by two different but highly homologous genes in a cell type-specific manner. FcγRIIIB is a low-affinity, GPI-linked receptor expressed by neutrophils and eosinophils, whereas FcγRIIIA is an intermediate affinity polypeptide-anchored transmembrane glycoprotein expressed by a subset of T lymphocytes, natural killer (NK) cells, monocytes, and macrophages. The FcγRIIIA receptor is involved in phagocytosis, secretion of enzymes, inflammatory mediators, antibody-dependent cellular cytotoxicity (ADCC), mast cell degranulation, and clearance of immune complexes. FcγRIIIA has an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain and delivers an activation signal in the immune responses. Aberrant expression or mutations in this gene is implicated in susceptibility to recurrent viral infections, systemic lupus erythematosus, and alloimmune neonatal neutropenia. In humans, it is a 50 -70 kD type I transmembrane activating receptor. The FcγRIIIA cDNA encodes 254 amino acid including a 16aa signal sequence, 191 amino acid ECD with two C2-type Ig-like domains, five potential N-glycosylation sites, a 22 amino acid transmembrane sequence and a 25 amino acid cytoplasmic domain.
β-2-Microglobulin (B2M) is a secreted protein with 1 Ig-like C1-type (immunoglobulin-like) domain which belongs to the beta-2-microglobulin family. B2M component of major histocompatibility complex (MHC) class I molecules, involved in the presentation of peptide antigens to the immune system. Polymers of beta 2-microglobulin can be found in tissues from patients on long-term hemodialysis. B2M is a protein found on the surface of many cells and plentiful on the surface of white blood cells. Serum B2M concentration is increased in renal diseases, various malignant diseases and some inflammatory and autoimmune disorders. B2M may adopt the fibrillar configuration of amyloid in certain pathologic states. The capacity to assemble into amyloid fibrils is concentration dependent. B2M has been shown as a marker for monitoring inflammatory disease activity and it appears likely to have a destructive role in amyloidosis-related arthritis. B2M might be involved in the OA (osteoarthritis) pathogenesis. Defects in B2M are the cause of hypercatabolic hypoproteinemia. Affected individuals show marked reduction in serum concentrations of immunoglobulin and albumin, probably due to rapid degradation. B2M could be a potential therapeutic target in ovarian cancer.
Fibroblast Growth Factor 21 (FGF21) is a growth factor that belongs to the FGF family. FGF family proteins play a central role during prenatal development and postnatal growth and regeneration of mamy tissues, by promoting cellular proliferation and differentiation. FGF21 is a potent activator of glucose uptake on adipocytes, protects animal from diet-induced obesity when overexpression in transgenic mice, and lower blood glucose and triglyceride levels when therapeutically adiministered to diabetic redents. FGF21 is produced by hepatocytes in reponse to free fatty acid stimulation of a PPARa/RXR dimeric complex. This situation occurs clinically during starvation, or following the ingestionof a highly-fat/low-carbohydrate diet. Upon FGF21 secretion, white adipose tissue is induced to release free fatty acids from triglyceride stores. Once free fatty acid reach hepatocytes, they are oxidized and reduced to acetyl-CoA. The acetyl-CoA is recombined into 4-carbon ketone bodies, release, and transported to peripheral tissue for TCA processing and energy generation.
Hepassocin, also known as hepatocyte-derived fibrinogen-related protein 1 (HFREP-1), is a liver-specific secreted protein belonging to the fibronogen superfamily, whose members share a fibrinogen domain at their C-termini. It is secreted by the liver and functions as a mitogen for hepatocytes. Hepassocin may play a role in the development of hepatocellular carcinomas. Hepassocin is a disulfide-linked homodimeric protein with a C-terminal fibrinogen domain. It is reported that it is a major immune inhibitory ligand of LAG-3 .
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