Re: How does the immune system distinguish between Normal&pathogenic flora?

We do have a lot of microbes that inhabit our mucosal surfaces, as Anisha aptly outlines. The human body "contains" higher numbers of bacteria than actual human cells! The skin is a special barrier that I won't touch upon (pun intended) here, but the question of tolerance versus reactivity to microorganisms on our mucosal surfaces is a fundemantal aspect of selective immunity. A lot of researchers have tackled this issue in the past decade and we have made significant headway.

Several scientists, notably Polly Matzinger, had formulated a "danger" hypothesis in the early 90s. This basically postulated that "foreign" antigens alone would not be sufficient to activate an immune system. A second stimulus, the elusive "danger" component would be required for activation. In parallel, vaccines almost always contain such a component in addition to the proteins (for example, alum for the influenza virus in the flu shot) that raise antigen-specific immunity. It was not known how these substances helped boost the vaccine response measured in antibody titers or T cell response.

So, what kind of molecules would elicit this "danger" response and why would the immune system have evolved in this fashion? The late Charlie Janeway at Yale was one of the first to postulate (in a seminal speech at Cold Spring Harbor in 1989) that immune systems should in theory have evolved to utilize receptors that could recognize "patterns" in invading microorganisms that would not be found in mammalian cells. Later work by Janeway, Medzhitov and others showed that these receptors do indeed exist. Initially found to control fungus infection in flies (and named Toll, loosely meaning 'cool' in German) their counterparts in mammals could recognize diverse molecular patterns of "danger", such as lipopolysaccharides, double-stranded RNA, flagellin, and CpG (bacterial) DNA.

When bacteria stay on their own side of the barrier, so to speak, little of these products find their way into tissue and end up being processed by resident antigen-presenting cells (such as various dendritic cell types). When there is a breach, and a rapidly expanding population of microbes taking advantage of the new niche, a lot of these molecules are made and thereby detected by the local immune cells. In addition, dying cells of the body also release "danger" signals that add to this response. The delicate balance between tolerance and immune response is compromised in many diseases, from as simple as diarrhea to chronic inflammatory conditions such as Crohn's disease.

In summary, Toll-like receptors and other molecules that can detect the "fingerprints" of microbes and assess local tissue damage are able focus the immune response to deal with invasions of the mucosal tissues when the prevailing "peace" between the body and microbes may turn to local "skirmishes" or all out war.