Cell Talk

office_gossip-web1Hello again fellow information addicts. Did you have a good week? Well mine was just bursting with fruit flavor (try not to look too far into that). Anyway, after our last chat about the role of our immune system in allergic response, Allergies Oh My, I felt this incredible need…I mean like a deep and real need to talk about another wild topic in immunology, communication, as in cell to cell communication. Believe it or not, our white cells are quite chatty with one another. They don’t talk about reality shows, how Sarah’s new hair style is “all wrong for her” or what horse they’re betting on at the track in Charleston this payday weekend. It’s a non-verbal communication (can I say body language without it being a pun?). No, when our cells talk to each other they only want to know one thing, “are you one of us?” That is the very definition of immunity, being able to distinguish the sharks from the minnows, what scientist refer to as “self from non-self.” Cells accomplish this without secret handshakes or gang colors. Instead, each cell comes equipped with a special membrane bound receptor that displays protein epitopes, portions of particular proteins that cell in question makes.

So the white cells are like Penn State campus security, floating around, approaching sketchy looking cells it hasn’t seen on campus before going “alright kid, let’s see some ID. What’s your major? Ok ok…looks good, move along.” Every nucleated cell comes equipped with a membrane bound receptor, a complex of proteins referred to as a Major Histocompatibility complex, or MHC. These receptors operate by aide of two major biochemical pathways, MHC I and MHC II. I think of them as having different versions of software. In fact, the nature of these receptors is profoundly Star Trek-ish and sophisticated. Here’s the situation…

See that orange socket wrench poking out of the cell? That's the kind of receptor we're talking about.

See that orange socket wrench poking out of the cell? That’s the kind of receptor we’re talking about.

Cells have membranes made up of a ballpit of proteins, fats, carbohydrates, and lipids that form this semi-solid layer that keeps their insides from spilling out onto the dance floor. So anything that cell needs to take in must pass through the membrane. This includes information. For a cell, information comes in a molecular form just like everything else that has to be taken into the cell. There’s no high speed internet, no Wi-Fi, no Skype. It’s like having your mail served to you on a dinner plate along with your chicken tenders. So in order to communicate to a cell you would need to A) keep that message painfully simple and B) convert that message into a molecular form that can be readily passed through the membrane. One form of cellular message that white cells use are referred to as cytokines. Cytokines are both released by white cells and taken up by them and they trigger vital immune responses. For example cytokines are responsible for attracting white cells to the site of an infection as well as switching them on and kicking them into action. Let me put it this way, a white cell without cytokines is like a police department with no dispatcher. Now back to receptors.

MHC II pathway

This version is typically found on white cells that act as antigen presenting cells or, as I like to call them “instigators.” These are cells like macrophages, monocytes, and dendritic cells that spend their time gobbling up any weird cell, bacterium, viral particle, or whatever that doesn’t identify itself in a timely fashion or flash the right ID. After the cell has devoured it’s prey and digests it with its cellular stomach (lysozyme/peroxisome) the organic bits and pieces like amino acids, lipids, etc. get recycled and distributed. Some of those bits, epitopes get attached to the MHC II receptor.

I'll bet you didn't know your cells were pre-labelled

I’ll bet you didn’t know your cells were pre-labelled

The cell has numerous receptors in fact and in this case the receptor is inside of the cell in the cytoplasm where all the action is happening. The MHC II/epitope complex makes it’s way up to the membrane surface of that antigen presenting cell for display like an Applebee’s appetizer sampler platter. Well, it’s a bit more morbid than that because remember, this is a sample of the enemy (very Silence of the Lambs). So it’s floating around flashing the ID to other white cells “have you seen this guy before?” until it meets a T-cell (a CD4 cell to be exact) that says “oh yeah, I’ve met this guy and he’s a total D-bag. I’ll let everybody know.” In the case of an adaptive immune response that white cell will seek out a B-cell holding the same epitope, release cytokines to activate that B-cell to produce antibody against the invading microbe.

MHC I pathway

This version is super friggin cool. It’s found in every single nucleated cell in the body. It’s function; display protein epitopes of what what that cell is producing. Yup, it’s like a show and tell receptor for cells. The cells say “look what I made in arts and crafts today.” If it’s something our white cells recognize than everything is gravy. Oh man, but if that white cell doesn’t like what it finds..well all hell kind of breaks loose. There is a no nonsense kind of white cell called a Cytotoxic T-cell, or CD8 killer. When it discovers foreign epitopes on a cell’s MHC I receptor it intiates a kind of self destruct command for that cell called apoptosis. To understand this you need to understand something about viruses. Viruses ONLY survive inside of a host cell…key word “inside.” They don’t just hangout inside the cell and watch sports center. They are up to no good, using the cell’s nuclear machinery and endoplasmic reticulum to produce viral proteins and essentially make new viruses. Once a cell is hijacked and turned into a viral production line there’s no going back. So like the sad scene in a zombie apocalypse film the CD8 takes the poor, infected cell out of it’s misery, which halts the replication of the viral particle. Our immune system evolved in this way because it has witnessed what viruses are capable of and has learned not to hesitate to pull the trigger.

Well my friends I’m off to go make a difference (get Thai food). As always stay curious, stay classy, and never stop learning 🙂

Let’s Talk Immunity

professional bow tie models look just like bouncers don't they?

professional bow tie models look just like bouncers don’t they?

This episode of Forgotten Physiology accepts the challenge of explaining cell mediated immunity in 5 minutes without the aid of caffeine! Grab some popcorn and don’t miss the action.

The body is a lot like an exclusive club in downtown D.C. No one gets in without an invitation (MHC receptor…every self respecting cell has one) and I do mean NOBODY. There are bouncers always watching the entrances and the exits (Dendritic cells, Macrophages) for shady characters looking to start trouble (viruses, bacteria, fungi, parasites). They are also constantly carding at the door for minors (immature red and white cells) or anyone who has an expired membership card (malformed cells, tumor cells, or any infected cells that make the wrong receptor).

Now these bouncers are pretty fierce. Good guys, but you don’t want to ever cross them because they will go Green Hulk on you expanding to sometimes 3 times their normal size and will literally (no really literally) eat you alive. They also have one hell of a temper and not only will they eat you but they’ll steal your wallet pass your picture to their friends so that anyone who even looks like you gets the gangland treatment. (sampling antigenic determinants from the bacterial cell for display to helper Tcells)

A Day in the Life of the Macrophage (cell-mediated immunity)

this picture is totally how your white cells look under 40x mag..trust me :)

this picture is totally how your white cells look under 40x mag..trust me 🙂

Let’s ride along with the macrophage. This guy never stops working he pounds the pavement patrolling our peripheral blood circulation for strangers and shady characters (pathogens, toxins, foreign substances) that don’t belong and when it finds them it swallows them whole and digests them with a kind of industrial strength cellular stomach called a lysozyme, but it doesn’t stop there. Our immune system hasn’t learned about the infection yet it hasn’t hit the news. The macrophage must now present that antigen (foreign substance which elicits an immune response) to another kind of specialized cell the T-cell. That’s what a macrophage does it acts as an antigen presenting cell (APC to his friends). The way it does this is by binding some of the peptides of that antigen it swallowed with its own proteins (MHCII class) displays them on the surface of its membrane as receptors. Our macrophage now takes a little field trip to a nearby lymph node (a hot spot in town where all the young lymphocytes hang out) but he’s not just looking for any ole T-cell. Macrophage can only present antigen to a cell with matching receptors for it. He’s looking for “Misses Right.” Warning this next part is a little graphic. If and when our hero finds a T-cell they dock receptors (MHC II complexed with antigen T-cell’s CD4 receptor w/MHCII binding site) Macrophage passes along some IL-1 that stimulates that cell to switch on divide into daughter cells release its own IL-2 that stimulates those cells to divide. So the macrophage has now informed your T-cells, your effector cells about the infection and your T-cells produce an army of messenger clones all hard wired to manage the same infection.

Now the infection has reached the front page news. Meanwhile B-cell with the right receptors has encountered the same antigen that everybody is talking about. He has already processed the antigen bound it with his own MHC II protein. Now he’s watching for T-cell to switch him on, give him the software he needs (IL-2 helper cytokines) so that he can upgrade – switch from an IgM to a IgG antibody producing cell and divide into an army of plasma cell clones. So at this point you can imagine your lymph nodes are becoming a very crowded place and they are. Those lymph nodes begin to swell as thousands of activated lymph cells fight the active infection. These cells are short lived though many of your plasma cells spit out antibody and then die shortly after. Some of those cells live on inactive in your lymphatic system as memory cells. If that antigen returns they’ll switch back on and start spitting out high specificity IgG. This specialized antibody is many times more efficient at binding than the store brand IgM. Phew….now I need a nap. Until next time my friends. Stay classy and never stop learning.

Strep Poker

Don't you hate it when you have a sore throat and half of your face falls off? That's the worst.source:http://www.aurorahealthcare.org/yourhealth/healthgate/getcontent.asp?URLhealthgate=11535.html

Don’t you hate it when you have a sore throat and half of your face falls off? That’s the worst!

Not unlike blizzards or public radio telethon week, sore throats happen. Sure, you can eat all the right things, get plenty of exercise, wear a hat when it’s cold, and dry your hair when it is wet, but the honest truth is that sore throats will still happen. Whether it was the 5 yr old at the bank who never covered his mouth when he coughed or the fact that you never washed your hands before leaving the birthday party at Chuck E. Cheese, as far as your immune system is concerned, it is only a matter of time before an infection sets in. Thankfully, a number of safe, easy, and reliable testing methods have been developed in recent years to aid clinicians in identifying these elusive, agents of infection and help patients arrive at a speedy recovery.

A Storm on The Horizon 

Morning is a cruel mistress

Morning is a cruel mistress

We can always feel it coming can’t we…that scratchy feeling in our throat, the dull twinge in our ears when we try to swallow. Oh yes, it’s sore throat time. Stayed out a little too late last night didn’t you? DIDN’T YOU?! Now just look what you did. That’s ok. Surprisingly, it is our body’s own immune response that produces the bulk of the drama when it comes to the really nasty cases of strep throat, especially in cases of neglected or under treated infections. Once the bacteria is recognized by our macrophages (the border patrol of our innate immunity) a cascade effect of cytokines, or cellular signals are released that bring about a variety of changes. Not only are white cells called to the site of the infection for a phagocytic schmackdown (when bacteria are either engulfed by macrophages or tagged by protective proteins for certain death by osmotic implosion), but inflammation is also induced by those white cells that are called to serve.

Blame those naughty antigens

The distinct molecular attributes of the streptococcus bacteria, or antigens, are largely to blame. The antigens (in this case, membrane bound proteins and carbohydrates that elicit an immune response) on the surface of the bacteria kick the immune system into overdrive, producing chemical cytokines or cellular signals that induce white blood cell action and inflammation (Phew…that’s technical!).This is what produces the characteristic soreness, swelling, and redness at the site of the infection. This not only makes swallowing difficult and painful but, lymph node glands can also begin to swell resulting in muscle ache in the neck. Fever and chills may also accompany the infection, as well as nausea and vomiting often in response to the persistent pain and discomfort. In the trade we like to refer to these as flu-like symptoms.

Sources of Infection

The bacteria can be spread from person to person by droplets from the cough or sneeze of an infected person. That’s right people, cover your pie holes! It is also possible to pick up the infection after touching contaminated surfaces like door handles or keyboards and then touching your eyes, nose, or mouth whereby the bacteria can easily gain access to the upper respiratory tract. Strep throat caused by S. pyogenes typically effects children or anyone with a weakened immune system. The infection can clear up on its own, however in some cases, S. pyogenes infections can lead to further complications, such as scarlet fever, toxic shock syndrome, and glomerular nephritis.

Behind the scenes

Typically when clinicians test for strep throat they are looking for the bacterium Streptococcus pyogenes. That is not to say that other bacteria as well as viruses are not just as capable of causing upper respiratory infections, but when it comes to the characteristically red, inflamed sore throats, in this region of the world anyway, it is S. pyogenes that usually gets called in for questioning. It is a handsome, frisky Group A, Beta-hemolytic strain of bead like bacteria that can produce mild to aggressive infections. “Beta hemolytic” refers to the ability of the bacteria to completely rupture (lyse) red cells on a culture plate, demonstrating a distinct, clear zone of red cell destruction. If you were to hold up an agar plate to the light it looks like someone took their thumb and rubbed the gel away where the Strep had been growing. Just think about the kind of damage something like that can do in your throat…ewww. That zone of hemolysis is a diagnostically reliable behavior that lab folks use to pick our star bad boy out of the line up.

Blinded by Science – Testing Principle

I hear lipstick models have really bad eyesight

I hear lipstick models have really bad eyesight

There is a bargain bin of strep testing kits out there in the biotechnology market. They all tend to work off the same testing principle of immunofixation whereby a sought after antigen (in this case the S. pyogenes membrane bound carbohydrate) is bound to specific antibodies within the testing media. There is also a color indicator in the mix that forms a unique complex which displays the presence of that antigen. The color change is then interpreted as a positive result. It is way less dramatic and not nearly as fun as mystery flavor koolaide. These tests are limited by sensitivity, meaning that an individual can in fact have a Strep infection that is below the detectable limits of the test. This is why it is a good practice for the physician to order a follow up culture for negative rapid strep screens.

Penicillin to the rescue!

As mean as sore throat infections can be they are often easily treatable. If they do not clear up quickly enough on their own we can typically zap them with antibiotics in the form of our favorite cell wall attacking antibiotics like penicillin, amoxicillin, or any taster’s choice cephalosporin on the market. Just be sure to take your full prescribed dose. Those microbes are sneaky and like to play dead. Under treating an infection is the perfect real world example of “what does not kill us, makes us stronger” except in this case it’s the Strep that can come back stronger. Of course, antibiotic resistance will have to wait for another article.

Stay classy my friends and never stop learning.