Antibodies: Defend!

Antibodies: Defend!

Once a parasite makes it past our outer defences, it encounters some seriously sophisticated weaponry. One of these is the ever-shifting antibody, my seventh structure of Christmas.

Every large organism – you included – is just a feast laid out for any parasite (bacteria, virus or beastie) clever enough to break in and access its carefully amassed energy. Throughout the Billion-Years’ Evolutionary War between hosts and parasites, the host has always been on the defensive, endlessly innovating to fend off invaders.

The biggest defences are the most obvious: tough outer barriers, sometimes flexible (e.g. skin) that block most parasites from entry. Others are more action-based: surfaces coated with mucus, which is constantly being moved about and shed along with the parasites it traps.

In the early days of vertebrate evolution these barriers were great, but every time a new defence evolved, some wily viruses, bacteria or parasites would find a way around it to devour these delicious, ponderous collections of cells. So the defenders eventually came up with a new approach: mounting a targeted defence that can adapt as the invader changes.

Upping the hit rate

Our distant ancestors managed this by combining two things: surveillance and targeting. The surveillance part is an internal ‘parasite control’ mechanism, whereby defence proteins recognise specific types of bugs. That triggers a targeted cellular attack – like sending nanoscale cruise missiles to a specific location.

But the hit rate is limited by how precise that recognition can be – so if it’s going to work, it’s got to be very good indeed. As the cholera toxin structure demonstrates, the parasite never stops coming up with tricks to get in – parasites play for keeps.

Eventually, the defenders evolved a radical innovation that ups the hit rate considerably: Deliberately ‘scrambling’ the defence protein’s recognition site, and amplifying the changes that are successful.

The shuffle

The new scrambling mechanism needed two things in order to work: strength and utility. The structure of the defence protein had to be a scaffold strong enough to tolerate the scrambling. And the information had to be scrambled in such a way that it was mainly productive. (Often scrambling just leads to a useless mess, but this scrambling needs to deliberately change recognition sites.)

Somehow those early, fishy vertebrates cracked it. Today’s structure, from a descendant of one such fish (in fact, ourselves), is the antibody: a protein with a very successful ‘scrambled defence’ component.

Picture the antibody as a strong Y-shape: two arms reaching up, each hand a barrel with long, fat fingers. The barrels (beta sheets) are constant – but the fingers upon them get scrambled. They are different for each, individual antibody.

To achieve this amazing feat, the genomes in the cells that make antibodies direct an elegant card-shuffling process for the region that encodes the fingers:

  • They randomly choose one V segment from around 50.
  • Then they choose one D segment from 30
  • They then also have 6 J segments to choose from.

This is almost outrageously simplified but it gives you the general idea. (As an indicator of the complexity, there are three places in the genome that do this for antibodies and another that handles it for T-cell receptors; also, different people have different numbers of these places…)

The right tool for the job

Antibodies are the only known case in vertebrates that involve purposeful editing of our own genome. In fact, the enzymes our distant ancestors drafted in do the editing were, ironically, co-opted from a DNA parasite. The product of this editing is a mind-boggling diversity of possible fingers and hand arrangements, with each finger able to bind to a different foreign agent (often, but not always, proteins).

Importantly, each cell only does one re-arrangement (there is another, very clever trick involved here that I won’t go into). So each of these immune cells (B cells, a type of white blood cell) has one–and only one–configuration of fingers.

Our bodies can make proteins that can grab on to anything, which is perfect if you’re just thinking about targeting parasites and winning the arms race. But with great (cruise-missile-like) power comes great responsibility, so a strong system of checks and balances has to be set up to avoid the one thing we don’t want: self-destruction!

We somehow need these antibodies to only target the cells that attack us.

Handle with care

All vertebrates have specialised organs to screen potentially lethal cells, and admit only the ones that won’t attack us. In mammals, central control for this is in the thymus: a fatty organ just above the heart. But quite how this is managed so well is a mystery.

Amazingly, thymus epithelial cells are able to switch on pretty much every gene in the human genome, and to make proteins without destabilising the cell itself. That is quite an achievement, considering they can make proteins from every cell type.

Once a full set of primed, “ready-to-attack-anything-that-is-not-self” proteins are assembled, another specialised mechanism is employed to activate this army.

Naïve immune cells display their finger combinations on their surfaces, and redirect anything the fingers catch into the cell, where they are promptly chopped up. (This is going on all the time.) The screening process prevents them from catching anything they recognise as being “from its own body”. When it does catch something, it should be an unwanted guest.

“I never forget a face…”

Another piece of screening-and-activation wonder deserves its own post, but is worth summarising here.

When the entire immune system realises that there is an infection, and that this particular B cell is capturing part of the unwanted guest, the cell gets a signal to multiply massively. During that growth two things happen:

  1. Most of the cells go into attack mode, releasing the antibody into the blood stream to tag the parasite for destruction.
  2. A subset of the cells deliberately recedes and transforms into the ‘molecular memory’ of this particular unwanted guest.

This cellular memory is the reason why vaccination and immunity works. We remember the exact combination of successful structural ‘fingers’ that caught a particular virus or bacterium, and make more when we need them.

It is an approach to keeping us free from infection that has worked quite well for millennia. I, for one, am grateful.

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