Third Point: Hey Look, Someone Sent Me a Cytokine
Imagine needing 50 different ways to communicate. You’d think there must be a lot of different kinds of cells that are using cytokines to try and communicate with each other. Actually, there are just a few kinds of cells that send and receive cytokines and most of them are what we commonly call “White Blood Cells”, or WBC’s. There are several kinds of WBC’s (also called leukocytes). This means that “white blood cell” is not a specific term, it refers to a general group of blood cells. In high school biology we learn that they ward off disease. From there it gets more complicated. Here’s a list of the kinds of white blood cells
, with subset types and AKA’s:
…..…... T Lymphocytes (NKT and Alpha Beta TCR Cells)
…………… CD4+ T Cells (Inflammatory T Cells)
……………….. T Helper 0 Cells
……………….. T Helper 1 Cells
……………….. T Helper 2 Cells
……………….. T Helper 3 Cells
……………….. Tr Cells
……………….. Tr1 Cells
…………… CD8+ T Cells (Cytotoxic T Cells, CTL)
………. B Lymphocytes
…………… Plasma B Cells
…………… Memory B Cells
………. Natural Killer Cells (NK Cells, Null Lymphocyte Cells)
………. Dendritic Cells
Neutrophils are produced in bone marrow and work their way around the bloodstream and eventually exit the bloodstream and into infected tissue. They are a primary defense against bacterial infection. The body produces more neutrophils when there is a bacterial infection. Here’s another website that discusses neutrophils from an MS perspective.
Neutrophils are rarely implicated in MS except for in Marburg Disease
, which is very rare.
The functions of eosinophils are not fully understood. When an antigen enters the body lymphocytes and neutrophils attract eosinophils to the site where they kill the invading antigen. Their primary function is to immobilize parasites by attaching to them. Eosinophils are rarely implicated in MS except for in Devic Disease.
Basophils make up only a small portion of the number of white blood cells, representing only 0.5% of the leukocyte population. They release histamine and other chemicals that act on the blood vessels to mediate inflammation and allergic responses. Histamine attracts other white blood cells to the inflamed site. Although basophils are rarely implicated in MS, here is one theory
of the cause of MS that involves basophils cells.
Together the three kinds of cells; Neutrophils, Eosinophils and Basophils make up the group of WBC’s called Polymorphonuclear Granulocytes. Here is a link
to a page that has more information about these cells.
T Helper 0 Cells
While it is widely thought that these cells are simply precursors of Th1 and Th2 cells, it has been shown that in the right environment
Th0 cells can be become a prevalent population of cells. General understanding is that these cells are derived from naïve Th cells (also called ThP) and then differentiate to become either type Th1 or Th2 cells. Differentiate is used to describe the process that a cell goes through in acquiring a type. Here’s a simplified diagram
and here’s a more complicated diagram
and narrative about this.
T Helper 1 and T Helper 2 Cells
I’ve tried to describe these separately, but it’s complicated. Most everything on the internet discusses Th1 and Th2 cells together in a compare and contrast sort of way. First of all Th1 cells participate in something called Cell Mediated Immunity.
Cell Mediated Immunity is a process whereby Th1 cells recognize an antigen and then begin to divide, thereby making more Th1 cells. The Th1 cells have the ability to activate other cells like macrophages that act directly with the antigen to kill it. Humoral Immunity
is a process whereby a B cell recognizes an antigen and then divides to produce plasma cells. The plasma cells produce antibodies that destroy the antigen. The Th2 cell participates in the Humoral Immunity
response by activating the B cells to divide and secrete antibodies. While there is still uncertainly about the exact cause and process of MS, it is a widely accepted hypothesis that Th1 cells are part of the disease process and that Th2 cells help to slow the disease process. More simply, Th1 is thought to be bad and Th2 is thought to be good. More on this later. Here’s one more link
on the topic of T Helper cells.
Tr Cells, Tr1 Cells and T Helper 3 Cells
There is very little information on the internet about these cells. The role of these cells is thought to be immune response suppression. T-regulatory cells (Tr) appear to play a role of inhibiting Th1 and Th2 cells. T-regulatory 1 cells (Tr1) appear to be similar to Tr cells. Th3 cells are prevalent in the intestines. Here is another link
to an abstract that briefly discusses these cells. These cells do not appear to have a significant known role in MS at this time.
CD8+ T Cells
CD8 T cells are sometimes called cytotoxic cells because they recognize infected target cells and kill them. CD8 T cells recognize bits of protein on the surfaces of other cells. If a CD8 T cell recognizes foreign proteins on another cell surface, it generally kills the other cell, since the foreign proteins mean that the cell has been infected with a virus, an intracellular bacterium, or some such invader. The CD8+ cell does this with proteins it makes called perforin and granzymes. The CD8 T cell stores the proteins in bubbles, and when it's time to kill a target cell, the CD8 cell forms a tight connection with the target and blows the bubble out at it. Perforin forms holes in the target cell's membrane, which lets the granzymes in. The granzymes then start a self-destruct cascade in the target cell and force it to kill itself in a process called apoptosis
There are two kinds of B Lymphocytes, Plasma B Cells and memory B Cells. Plasma B Cells secrete antibodies (Ab) which affect the destruction of antigens (Ag) by binding to them and making them easier targets for phagocytes. Memory B Cells are formed specific to the Ag(s) encountered during the primary immune response. Memory B Cells can live for decades and quickly respond to a second exposure to the Ag. B Cells can multiply via signaling
from CD4+ T Lymphocytes. Ab’s are also called immunoglobulins (Ig). There are 5 kinds of Ig’s; IgG, IgM, IgA, IgD and IgE. One important distinction of B Cells is that they don’t attack Ag’s directly as T Cells do rather, they produce Ig’s that do the attacking. This process is called Humoral Immunity.
Natural Killer Cells
There's another type of lymphocyte called an NK cell, which is short for natural killer cell. They are also called Null Lumphocyte Cells.
They are not NKT cells, which sounds similar. They are not T cells. NK cells function in a similar way as CD8+ T cells, except that they do not need activation time before they can kill as is required of CD8+ T cells. Meaning, there is no "lag" phase of clonal expansion for NK cells to be active as effectors, as there is with antigen-specific T and B lymphocytes. Thus NK cells may be effective early in the course of viral infection, and may limit the spread of infection during this early stage, while antigen-specific lymphocytes are being recruited and clonally expanded. NK cells recognize their targets in a slightly different way, they see families of receptors and proteins and generally recognize cells that are showing signs of stress or that display signs of pathogens.
While, by contrast, T cells recognize very specific pieces of proteins on cell surfaces. The nature of the NK cell receptor (or receptors) that confer this selectivity of target recognition has not been clearly defined, but it has been shown recently that the expression of "self" MHC I molecules
inhibits NK lysis
of target cells.
Much has been learned about Dendritic cells since their discovery
in 1973. It has been recently discovered that there are two different kinds of Dendritic cells. They are often referred to as DC1 and DC2 cells. Unlike many other WBC’s, DC1’s and DC2’s do not have an immediately common lineage, wherein DC1 and DC2 cells result from differentiation in the maturing of a common blood cell. The lineage of DC1’s is said to be Myeloid which are a type of cell that can also mature to be a Polymorphonuclear Granulocyte or a Monocyte type WBC. The lineage of DC2’s are said to be Lymphoid which is the type of WBC that can mature to be a T cell or a B cell. It is important to note that the classification of a Dendritic cell as Myeloid or Lymphoid
is not related to whether it is a mature or immature cell.
Immature Dendritic cells are derived from bone marrow
, enter the blood and generally find their way to the skin or other tissues where they come into contact with antigens which they consume and present
to other WBC’s like T and B cells. When a Dendritic cell matures, it starts presenting the antigens to other white blood cells which “programs” them with a “picture” of what the foreign invader is like so that when the white blood cell finds another like cell it will know to kill it. Researchers are trying to figure out how to use this functionality to create a cancer vaccine.
As Dendritic cells mature they appear to have a T-helper cell bias.
Myeloid DC1’s tend to have a Th1 bias, meaning they tend to communicate signals that cause Th0 cells to differentiate towards Th1. Similarly they tend to facilitate cellular mediated immunity.
Similarly, Lymphoid DC2’s tend to have a Th2 bias and they tend to facilitate antibody production
In case you hadn’t noticed I got very interested in Dendritic cells. Science is fascinated with them. Here’s a few more links that include stuff about DC’s.
Dendritic Cell Maturation
Glatiramer Acetate and Dendritic Cells
Glatiramer Acetate Promotes Th2 Cell Development and Increased IL-10 Production Through Modulation of Dendritic Cells
Immunoregulation of Dendritic Cells
Dendritic Cells Under Investigation in Autoimmune Disease
Everything you read about Macrophages will talk about “Phagocytosis”. So lets deal with “Phagocytosis” first. Phagocytosis
is the process of consuming and digesting debris like damaged or dead cells and microrganisims that don’t belong in the body for one reason or another. Macrophages phagocytize (meaning engulf or eat) antigens. This is one of the key roles of the Macrophage. The life of the Macrophage begins in the bone marrow and they enter the blood as Monocytes. When they mature and migrate to tissue they become Macrophages. They can live in tissue for years. Macrophages have unique names depending on the tissue in which they reside:
Ordinarily Macrophages are inactive, which is referred to as Resident Macrophages. There is a two stage process
for a Macrophage to get activated. It is first “Primed” by a cytokine then in a follow up action it is activated by an agent, such as bacteria. Recently this process has been described as Classic Activation, which is contrasted with Alternative Activation.
Classicly activated Macrophages are thought to exhibit Th1-like tendencies and Alternatively activated Macrophages are thought to exhibit TH2-like tendencies.
Finally, Macrophages are Antigen Presenting Cells (APC’s). Dendritic Cells and B Cells are also APC’s. I realize after looking over my pile of printed up webpages on Antigen Presentation that I ought to take a small divergence from my original path (I was planning to start working on how the WBC’s use cytokines to communicate next) and present a more structured format for the WBC’s that is based on what they do. So first I’ll do a quick summary and then I’ll start on a second perspective on WBC’s based on what their roles are in the immune system.
Recap of White Blood Cells (WBC’s)
I’m just going to include some links here that I came across that I thought would be function as a nice summary:
Overview of the Human Immune System
The Immune System
The Immune System – An Overview
Explanation for Anybody
A VERY COOL Powerpoint!