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Physiopathological Implication of Genetic Variability
in the Complement Alternative Pathway.
My name is Santiago Rodriguez de Cordoba,
and I work at the Centro de Investigaciones
Biologicas in Madrid, Spain.
My disclosures are that I had been receiving fees from
Alexion Pharmaceuticals for participation in advisory boards,
expert meetings and teaching courses.
I'm also a founder-member and shareholder of Secugen S.L.
Complement is a crucial element of our innate immunity to fight infection.
It has an intrinsic ability to sense and react to pathogens.
But complement not only serve to eliminate pathogens,
also contribute to other physiological surveillance functions.
The most well known perhaps is clearance of Cellular debris and immune complexes.
But also participate in several other activities like tissue repair,
CNS development, and adaptive immune responses of lipid metabolism.
It is very important to realize that Complement is a double-edged sword.
Despite it's carefully controlled under normal circumstances to prevent host cell damage,
these regulatory mechanisms sometime become overwhelmed or misled,
and result in a number of serious conditions.
In this presentation, I will address the issue of complement genetic variability and
how that influences complement activity and regulation causing disease.
Complement genetic variability includes rare pathogenic variants.
In many cases, they are almost exclusive of
single individuals and with frequencies that are below one per thousand.
These rare pathogenical variants were in
the old days associated with primary deficiencies,
most of them interpreted as loss of function mutations.
Today, it is known that many of these rare pathogenic variants are gain of
function mutations that increase Complement activity and mediate host tissue damage.
In addition to rare pathogenic variations that are
common polymorphisms with frequencies higher than 1 percent.
There are many of these Complement Polymorphisms that affect
the functionality of the proteins encode by the genes.
In the old days, these Common Polymorphisms were
interpreted as marker of disease predisposition.
Today, they are considered functionally relevant and their combinations that we
would refer to them as Complotypes have an important implication in disease.
These common Polymorphism tend to be additive,
and the functional complementarity of
the different function reflect in the different activities of the Complotypes.