Wednesday, 16 November 2011

Aspergillosis and Congenital Immune Deficiencies - What we learn

Some of the many genetic deficiencies of our immune systems
Children with congenital immune deficiencies have been born having lost specific parts of their immune system and are thus vulnerable to infection by a number of infecting microrganisms.
At first thought we might think that such children are infected by any passing germ, and as such they become infected by the first microrganism that comes their way but this is not the case. Some immune deficiencies predispose children to one type of infection by a particular micro-organism and while others do not seem to be vulnerable to that 'bug' and instead are predisposed to other infections.

Why is this? Each genetic deficiency effects different parts of the immune system leaving some parts still active, so by looking at the species that can most commonly infect we can gain information on which parts of the immune system are most important for resisting each infecting organism and the types of infection. This principle is summarised in some detail in a recent paper by Bustmante where they review the patterns of fungal infections in children with congenital immune deficiencies.

Those parts of the immune system that are revealed to be particularly important for resisting infection by Aspergillus are phagocytes (mutated in Chronic Granulomatous Disorder, CGD) and more specifically their ability to produce superoxide ions. This presumably is one part of our immune systems that Aspergillus is partucularly sensitive to. This discovery of an Aspergillus infection of the lung of a young child and a clinical presentation of a granuloma seems to be a strong enough to point to a diagnosis of CGD if it is not already susected, so close is the association between this pathogen, infection of young children and CGD.

Another genetic defect strongly associated with serious Aspergillus infection is Hyper IgE syndrome. Here we see mutations in STAT3, a gene responsible for turning other genes off and on. This is a particularly complicated disorder as STAT3 respnonds to stumili from many different genes - it is a kind of central signalling post for a whole variety of systems, one of which is the immune system. Its involvement in our immune system is illustrated by one of the first noted featured of this syndrome - sufferers overexpress at least one part of their immune system - the IgE part. Normally a fast response system for infection IgE is designed to be produced quickly and then just as quickly fade away as more procise parts of the immune system take over the job of fighting the infection - it could be partly described as a broadly effective attack on infection that buys our bodies enough time for the slower but more effective parts of our immune systems to become fully activated.

The fact that Aspergillus can infect children that cannot control production of IgE might be another clue that IgE control is important for our resistance to Aspergillus, but as several (many) other genes are also involved we cannot yet come to such a clear conclusion.

These defects are giving us clues as to how Aspergillus and many other fungal infections (e.g.  Candida) can get past our normally efficient immune systems. The study of the defects will give us more clues in the future, and hopefully also give us ways to better treat children with these disorders.

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