Ophthalmology

Besides the traditional innate immune function in defense against pathogens by opsonization, cytolysis, or phagocytosis when the host adaptive immune system has not fully developed, the complement system is now known to serve as a bridge between innate and adaptive immunity, by playing an important role in adaptive immune responses involving T and B leukomonocytes.

Furthermore, the functions of complement system have extended to the maintenance of tissue homeostasis and cellular integrity as well as tissue regeneration. Complement is activated via three pathways, the classical, alternative and lectin pathways, where involves a series of initiation, cleavage and amplification steps. The complement proteins interact with one another in a tightly regulated manner.

Ophthalmology

In physiological conditions, complement activation is relatively low in favor of immune surveillance against foreign invaders and removal of damaged particles such as immune complexes, apoptotic cells, and cellular debris. However, the fact that the activated complement cannot discriminate self-tissues and foreign particles in pathological conditions, thus uncontrolled activation has the potential to cause substantial damages in various diseases, including ocular diseases,such as:

  1. Anterior uveitis
  2. Complement therapeutics for age-related macular degeneration (AMD)

The most typical complement-related ophthalmic disease is AMD, characterized by damages to the tissue complex composed of the retinal pigment epithelium, Bruch’s membrane, and choriocapillaris. There are several complements associated genes and genetic variants in AMD.

  1. Complement Factor H gene (CFH)

The CFH gene is the first identified susceptibility factor for AMD, which can encode CFH protein, a component of alternative complement activation pathway. The detailed genetic evidence revealed an association of AMD and polymorphisms of the CFH gene and CFH receptors genes (CFHR1 and CFHR3). The Y402H polymorphism, found in the ninth exon of the CFH gene, has been shown to induce differences in CFH’s affinity to glycosaminoglycans, malondialdehyde, and to oxidize low-density lipoproteins (oxLDL), what's more, Y402H variant is responsible for the increase in AMD risk. A deletion of the CFHR3 and CFHR1 genes are closely related to the lower risk of AMD.

  1. Complement Factor B gene (CFB)

CFB gene encodes the full-length CFB protein, which participates in the alternative pathway through forming part of C3 and C5 convertase enzymes. CFB polymorphism R32Q is associated with the protection from AMD, due to the less efficient formation of the C3 convertase. In AMD patients, a less efficient complement system is more advantageous. Another variant of CFB, L9H, is independent of R32Q and was found to be associated with protection against AMD.

  1. Complement Factor I gene (CFI)

As a cofactor with CFH, CFI is essential for the inactivation of C3b. Non-coding polymorphisms adjacent to the gene and in an intron of CFI are associated with altered risk of AMD.

The regulatory role of complement regulator factor H-like protein 1 (FHL-1) in human Bruch's membrane.

Fig.1 The regulatory role of complement regulator factor H-like protein 1 (FHL-1) in human Bruch’s membrane. (Clark, et al. 2014)

The complement system plays a central, causative role in the pathogenesis of the ophthalmic disease, especially in AMD. So the complement components have possibilities for genetic risk prediction and clinical trials of novel therapies.

Creative Biolabs provides a series of therapeutic antibodies, inhibitors, soluble complement regulators, as well as customized services for complement-associated ophthalmology diseases. We offer a great number of complement-related products in a rapid and cost-effective manner. If you are interested, please feel free to contact us for more details.

Reference
1. Clark, S. J.; et al. (2014). Identification of Factor H–like Protein 1 as the Predominant Complement Regulator in Bruch’s Membrane: Implications for Age-Related Macular Degeneration. The Journal of Immunology. 193(10), 4962-4970.

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Questions & Answer

A: Challenges include the need for better drug delivery methods, potential off-target effects, and the heterogeneity of ophthalmic diseases. Researchers are exploring innovative drug delivery techniques, refining drug specificity, and conducting extensive preclinical studies to address these challenges.

A: Yes, gene therapy and stem cell-based approaches are being explored to develop novel complement therapeutics. These experimental methods aim to address the root causes of complement system dysregulation in ophthalmic diseases.

A: Experimental approaches include intravitreal injections, sustained-release implants, and gene therapy to deliver complement inhibitors. These approaches aim to address issues like drug penetration and the need for prolonged therapeutic effects.

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