Inflammation implicated in AMD activation

July 1, 2005

Fort Lauderdale, FL—All indications point to the fact that inflammation is involved in complement activation in age-related macular degeneration (AMD), based on the results of recent research. In addition, the phenotype of drusen in a rare disease, membranoproliferative glomerulonephritis type II, is similar to that in AMD.

Fort Lauderdale, FL-All indications point to the fact that inflammation is involved in complement activation in age-related macular degeneration (AMD), based on the results of recent research. In addition, the phenotype of drusen in a rare disease, membranoproliferative glomerulonephritis type II, is similar to that in AMD.

The biggest recent development is the discovery of a protein that regulates complement. The gene is HF1 or CFH (complement factor H) and has been associated with AMD in five studies.

All of these studies have focused attention on the 1q region of chromosome 1 and more specifically to a cluster of genes referred to as regulation of complement activation in the region 1q31-32. This region has a plethora of proteins involved in complement regulation, including HF1, its truncated splice variant HFL1, and H resembling proteins.

Factor H, Dr. Bok explained, is a plasma protein that regulates complement (group of proteins involved in attack of microorganisms and on innocent bystander cells) activation and is present in varying concentrations in the blood. Factor H, which exclusively regulates the alternative pathway of complement activation, is produced primarily in the liver and locally in the retinal pigment epithelium, neurons, and elsewhere at a number of sites. Complement is good because it is part of the innate immune system, but bad because it can get out of control, he pointed out.

Two immune systems Humans have two immune systems, the adaptive immune system with B and T lymphocytes, and the innate immune system, which does not need education as to what constitutes self and non-self. Complement is part of the innate immune system.

Three pathways of complement activation have been identified: classical, which involves a number of proteins that are involved in recognizing antibodies; the lectin pathway; and the alternative pathway, where factor H regulatory activity is carried out. All three pathways converge on cleavage of complement 3, producing complement 3b, which binds to cell surfaces and is controlled by factor H.

"This is a very important control point for factor H," Dr. Bok emphasized. The final common pathway is the assembly of the so-called membrane attack complex (mac), which forms pores in the membrane and the cell "exsanguinates." If the inactivation of factor C3b is regulated sufficiently, the attack complex is not formed.

Factor H is a highly complex modular protein with 20 modules called short consensus repeats (SCR). The consensus repeat SCR7 is a heparin and C-reactive protein binding (CRP) site. CRP activates the complement system, whereas factor H binds CRP and controls the complement cascade.

"All the recent buzz has been about an amino acid variant at SCR7, which constitutes a change in the sequence from tyrosine 402 to histidine 402," Dr. Bok said. "This is exciting, because now we have a way to test the function of this molecule to see if this change in amino acid sequence is related to dysfunction in factor H biology. For example, the binding properties of CRP could potentially change, and as studies have shown, there is elevated CRP in some patients with AMD."

Another exciting discovery, he said, is that smoking inhibits factor H. We know from epidemiological studies that there is as much as a five times higher chance of developing AMD when you are a smoker.

Other studies have found that drusen are loaded with inflammatory molecules, many of which are components of the complement cascade and heavily represented by components of the alternative pathway, Dr. Bok noted. In the drusen periphery, there is often a great deal of factor H, and in the center both factor H and the mac complex are observed by immunocytochemistry.