Possible Effects of Chemokine-like Factor-like MARVEL Transmembrane Domain-containing Family on Antiphospholipid Syndrome
Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by thrombotic or obstetrical events and the persistent presence of antiphospholipid antibodies (aPLs). These antibodies include lupus anticoagulant (LA), anticardiolipin antibodies (aCL), and anti-β2 glycoprotein-I (β2GPI) antibodies. APS can occur as a primary condition or in association with systemic lupus erythematosus (SLE) or other rheumatic diseases. While the presence of aPLs is critical to the pathogenesis of APS, it is not sufficient to explain the full spectrum of clinical manifestations. Therefore, further research is needed to uncover the underlying mechanisms of APS.
The chemokine-like factor-like MARVEL transmembrane domain-containing family (CMTM) is a group of proteins widely expressed in the immune system and potentially linked to autoimmune diseases, including APS. This review explores the possible roles of CMTM family members in the pathogenesis of APS, focusing on their interactions with immune cells and molecules.
The CMTM family consists of nine genes: CKLF and CMTM1-8. These genes are located on different chromosomes, with CKLF and CMTM1-4 forming a cluster on chromosome 16q22.1, CMTM5 on chromosome 14q11.2, and CMTM6-8 on chromosome 3p23. The proteins encoded by these genes exhibit characteristics of both chemokines and the transmembrane 4 superfamily (TM4SF). CMTM1 is most similar to chemokines, while CMTM8 resembles TM4SF, and CMTM2-7 exhibit intermediate characteristics.
CMTM family members are involved in various immune processes, including T-cell and B-cell activation, and have been implicated in autoimmune diseases. This review systematically summarizes the potential effects of CMTM on APS, focusing on their roles in immune cells such as neutrophils, dendritic cells (DCs), T-cells, and B-cells, as well as their interactions with inflammatory cytokines and adhesion molecules.
Chemokine-like factor 1 (CKLF1) is a member of the CMTM family with broad chemotactic activity. It can influence the expression of inflammatory cytokines and adhesion molecules through pathways such as nuclear factor-kB (NF-kB) and mitogen-activated protein kinase (MAPK). CKLF1 is involved in the maturation of DCs, activation of T lymphocytes, and neutrophil activation via the MAPK pathway. Additionally, CKLF1 interacts with C–C chemokine receptor 4 (CCR4), which is involved in the recruitment of activated leukocytes, particularly CD4+ Th2 lymphocytes.
CMTM1 may regulate Annexin A2, a protein involved in thrombosis, by modulating calcium (Ca2+) signaling. CMTM2 and CMTM6 are upregulated in neutrophils of APS patients, suggesting a role in neutrophil activation and the release of neutrophil extracellular traps (NETs), which are implicated in APS-associated thrombosis. Other CMTM family members, such as CMTM3, CMTM5, and CMTM7, influence platelet activation and accumulation, potentially contributing to hemostasis and thrombosis.
CMTM3 and CMTM7 are binding partners of B-cell linker protein (BLNK), which is crucial for B-cell receptor (BCR) signaling. CMTM3 enhances Rab5 activity, a key regulator of endocytic pathways, and may promote autoimmune diseases by enhancing BCR signaling. CMTM7 is essential for the development of B-1a cells, a subset of B-cells involved in the production of natural IgM and interleukin-10 (IL-10). Loss of CMTM7 results in reduced numbers of mature B-1a cells, leading to decreased IgM and IL-10 production and increased susceptibility to microbial sepsis.
In dendritic cells, CKLF1 plays a critical role in maturation and antigen presentation. It is highly expressed in monocytes and upregulated during the differentiation of monocytes into immature DCs. CKLF1 downregulates upon DC maturation, and its peptides, C19 and C27, enhance the antigen-presenting capability of immature DCs by upregulating HLA-DR and IL-12 secretion. CMTM3, also expressed in DCs, interacts with BLNK and may play a role in DC function.
Neutrophils are key players in APS pathogenesis, and their activation is associated with the release of tissue factor (TF) and NETs. CKLF1 exhibits chemotactic activity on neutrophils and activates them through the MAPK pathway. Anti-CKLF1 antibodies inhibit neutrophil infiltration by reducing the phosphorylation of p38, extracellular signal-regulated kinase (ERK), and c-Jun-N-terminal kinase (JNK), key components of the MAPK pathway. CMTM2 and CMTM6 are upregulated in APS neutrophils, further implicating CMTM family members in neutrophil activation.
T-cells are involved in APS through their activation by anti-β2GPI antibodies, which leads to endothelial cell activation, thrombosis, and placental injury. CKLF1, as a ligand for CCR4, may facilitate the recruitment of T-cells to sites of inflammation. It is upregulated in activated CD4+ and CD8+ T-cells and plays a role in the humoral immune response and germinal center formation by acting on germinal center T helper (GC-Th) cells.
B-cells are central to APS pathogenesis, as they produce autoantibodies such as aPLs. CMTM3 and CMTM7, as binding partners of BLNK, link BCR signaling and activate BLNK-mediated signal transduction in B-cells. CMTM7 is particularly important for the development of B-1a cells, which are involved in the production of natural IgM and IL-10. Reduced numbers of B-1a cells in CMTM7-deficient mice result in lower IgM and IL-10 levels and increased susceptibility to sepsis.
In summary, CMTM family members play diverse roles in the immune system and may contribute to the pathogenesis of APS through their effects on immune cells and molecules. CKLF1 influences the expression of inflammatory cytokines and adhesion molecules, promotes DC maturation, and activates T-cells and neutrophils. CMTM1 regulates Annexin A2 via Ca2+ signaling, while CMTM2 and CMTM6 are upregulated in APS neutrophils. CMTM3, CMTM5, and CMTM7 influence platelet activation and B-cell signaling, with CMTM7 being essential for B-1a cell development.
The potential of CMTM as a prognostic factor or therapeutic target in APS warrants further investigation. Understanding the mechanisms by which CMTM family members contribute to APS pathogenesis could lead to novel immunomodulatory treatments for this complex autoimmune disorder.
doi.org/10.1097/CM9.0000000000001449
Was this helpful?
0 / 0