Anp at world muscle society, page-2

WMS Thursday, 23 September 2021 CONGRESS DAY 2

LBP.20
ATL1102 treatment in non-ambulant boys with DMD modulates Latent TGF-beta-binding protein 4, a disease genetic modifier of DMD, and CXCL16
G. Tachas; C. Mueller; I. Woodcock; M. Ryan; N. Desem

About Latent TGF-beta-binding protein 4:
Latent transforming growth factor β (TGFβ)-binding protein (LTBP) 4, a member of the LTBP family, shows structural homology with fibrillins. Both these protein types are characterized by calcium-binding epidermal growth factor-like repeats interspersed with 8-cysteine domains. Based on its domain composition and distribution, LTBP4 is thought to adopt an extended structure, facilitating the linear deposition of tropoelastin onto microfibrils. In humans, mutations in LTBP4 result in autosomal recessive cutis laxa type 1C, characterized by redundant skin, pulmonary emphysema, and valvular heart disease. LTBP4 is an essential regulator of TGFβ signaling and is related to development, immunity, injury repair, and diseases, playing a central role in regulating inflammation, fibrosis, and cancer progression. In this review, we focus on medical disorders or diseases that may be manipulated by LTBP4 in order to enhance the understanding of this protein.


About CXCL16:

Chemokine (C-X-C motif) ligand 16 (CXCL16) is a cytokine which is part of the CXC chemokine family. The gene for human CXCL16 is on chromosome 17. The chemokine is larger than others in the same group and is made of a CXC chemokine domain, a mucin-like stalk, a transmembrane domain and a cytoplasmic tail that might contain a tyrosine phosphorylation site that could bind SH2. It has some unusual features that other chemokines do not have and is expressed as both a cell surface bound molecule and a soluble chemokine. Dendritic cells in the T cell zones of lymphoid organs and cells in the spleen produce CXCL16.

A number of subsets of T cells and NKT (natural killer T) cells bind and migrate as a response to CXCL16. It also interacts with the CXCR6 chemokine receptor (Bonzo) and its expression is induced by the cytokines IFN-gamme and TNF-alpha. CXCL16 is found in the thymic medulla, as well as some nonlymphoid tissues. This indicates that it has roles in thymocyte development and effector T cell trafficking. CXCL16 is expressed on the surface of APCs, and shed from macrophages. Its receptor CXCR6 might contribute to tissue localisation of plasma cells due to being binded to CXCL16, which is membrane-anchored. There are indications that the Bonzo receptor could be expressed in chronic inflammation.

CXCL16 is expressed strongly in gliomas, compared to a low expression in healthy brains. It is expressed by malignant and inflamed astroglial cells and shed to a soluble form, when it targets activated T cells and glial cells. CXCL16 could also play an important role in the development and progression of atherosclerotic vascular disease. A study showed that antibody-mediated blocking of CXCL16 ameliorated experimental immune nephritis, indicating that it could have potential pathogenic significance. CXCL16 and its receptor CXCR6 also promote the growth of human schwannomas, tumours of nerve sheaths, increasing proliferation and induced migration.

CXCL16 could promote interactions between DCs and CD8 T cells, as well as guiding T cell movements in red pulp in the spleen. CXCL16 might also have a unique role as a top MNC recruiter for rheumatoid arthritis and there could be additional therapeutic properties by targeting CXCL16, its receptor Bonzo, or its signalling pathways. CXCL16 plays an important role in T cell accumulation and stimulation in rheumatoid arthritis synovium. Anti-CXCL16 monoclonal antibody can reduce clinical arthritis score and infiltration of inflammatory cells and bone destruction.

The smooth muscle cells in human lesions express CXCL16, as has been shown through double-labelled immunohistochemistry. Large amounts are also present in bronchoalveolar lavage fluid. Additionally, decreased plasma CXCL16/SR-PSOX concentration is associated with coronary artery disease. This suggests that CXCL16 might have an atheroprotective function.

CXCL16 Human Recombinant is a single, non-glycosylated, polypeptide chain containing 89 amino acids. It is delivered as a sterile freeze-dried powder, shipped at room temperature. CXCL16 Mouse Recombinant is a single, non-glycosylated, polypeptide chain containing 88 amino acids, which is also shipped at room temperature and arrives as a sterile powder. It offers many research opportunities in a range of areas.