(1)
Department of Emergency Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
Immunology Basic Topics
Some aspects of the immune system are ready to defend us all the time – without any special experience or priming from other parts of the immune system. These aspects of the immune response are called “innate immunity .” Examples of the innate immune system are the skin and mucosal barriers of the body, and cells such as macrophages, neutrophils, natural killers, and the complement system.
These systems do not develop a “memory” for antigens they have seen in the past, and their response to the antigen will not improve with experience.
“Acute-phase reactants ” are part of the innate immunity system. When the macrophages encounter something that might be dangerous, they send out TNF, IL-1, and IL-6. This stimulates the liver to synthesize the acute-phase reactant proteins. Some acute-phase reactants can actually bind to bacteria, activating the complement system to kill the bacteria.
Immune processes that require prior experience with an antigen , or special priming of the cell to get its functions started, are called “adaptive” or “acquired immunity .” This type of immunity is possible only with experience with the environment, so it is acquired, rather than innate. For example, when a B-cell is primed to function by interactions with an activated helper T-cell , that is an example of acquired immunity. When a specific antibody is made to match an antigen encountered in the body, the immune system is “adapting” its response according to what it encounters – hence the term “adaptive” immunity .
Macrophages actually function as part of both the innate and adaptive immune system. If they encounter something that looks foreign to them, they eat it up – acting as an innate defense mechanism. Additionally, though, they present fragments of what they ate on their cell surface, in an MHC-II complex. This presentation serves to activate both B- and T-cells, making the macrophage a critical initiator of the adaptive immune response, along with other antigen-presenting cells.
B-cells can also present antigens to T-cells, in MHC-II complexes on their surfaces. Polymorphonuclear leukocytes (PMNs) , on the other hand, cannot present antigen, even though they seem similar to macrophages in terms of their eating habits.
The B-cell receptor (BCR) for binding antigens is incredibly skilled – it can be designed to recognize virtually any type of molecule. T-cells only see short peptides (in MHC-II complexes).
Major Histocompatibility Types
Generally speaking, MHC-II is found on cells of the immune system, and is used for presentation of antigen. MHC-I is usually found on nonimmune system body cells. It is used to recognize self, but can also display foreign antigens, in some cases (e.g., viral infection of a cell).
Immune Systems for Identifying & Destroying Threats
The Complement System
The goal of the complement system is to poke holes in foreign invaders that don’t belong in the body. Complement “fixing” means that complement complex has been attached to a cell’s surface, or to an antibody-antigen complex on the cell, and the cell is likely to now be lysed. The complement system is part of innate immunity.
There are three pathways of complement system activation. All of them culminate in formation of a membrane attack complex (MAC) .
The classic pathway (it was the first discovered – nothing really classic about it!) of complement fixation occurs when an antigen-antibody (Ag-Ab) complex gets the interest of complement factor C1. It attaches to the cell associated with the Ag-Ab complex.
After a series of conversions, C5b + C6 + C7 insert themselves into the cell membrane.
When C8 and C9 join them they are called the MAC. The MAC opens a hole in the cell’s membrane, lysing it. (A “MAC attack” – kind of like what you see at McDonalds®!)
The alternative pathway doesn’t require any help from antibodies. It is part of the innate immune system, and relies on the ready supply of complement factor C3b in the body. (Some C3 is spontaneously converted to C3b at a baseline level in the body. It is this C3b that is used in the alternative pathway.) Some bacteria, fungi, and clumps of IgA stimulate this complement to “fix” on their target without any other molecules being present.
The alternative pathway begins with complement factor C3b (the opsonin ), and then involves factors B, D, and properdin . It ends, as always, with a MAC attack (C5b + C6 + C7, joined by C8 & C9).
The third pathway is called the lectin pathway , because it is activated when polysaccharides present on pathogens bind to lectin or ficolin molecules of the body’s innate immune system. The lectin pathway successfully targets certain bacterial, viral, and fungal pathogens, including the RSV virus and Neisseria strains of bacteria.
The Story of Antibody-Mediated (Humoral) Immunity –
1.
A macrophage presents a bit of antigen in its MHC-II complex, on the cell’s surface.
2.
A helper T-cell binds to the macrophage, recognizing the antigen in the MHC-II complex.
a.
The helper T-cell starts to make:
i.
IL-2 T-cell growth factor
ii.
IL-4 B-cell growth factor
iii.
IL-5 B-cell differentiation factor
iv.
IL-6 B-cell activation/IgG production factor
3.
The matching B-cell is also activated by binding with the macrophage MHC-II complex containing the antigen, and through direct binding with the T-cell through surface receptors (CD40 & CD40L).
4.
Stimulation from IL-4 and other molecules leads the B-cell to activate into a plasma cell (immunoglobulin-secreting cell), and divide to provide many daughter cells, or to become a memory cell.
“T-cell-independent antigens ” are antigens that stimulate B-cells directly, without any assistance from the T-helper cells.
The Story of Cell-Mediated Immunity –
Type IV Hypersensitivity
1.
A macrophage and a bacterium meet. The macrophage eats the bacteria, and throws some pieces of it into an MHC-II on its own surface.
2.
The matching CD4+ T-helper cell wanders by, and binds with the macrophage MHC-II complex holding the antigen. The T-cell is “activated” by this process, and starts to proliferate. T-cell proliferation generates a “clone” of the same antigen-specific T-helper cell. T-cell activation and proliferation mainly occur when the T-cell is stimulated with IL-1 (from the macrophages) and IL-2 (from lymphocytes).
3.
The excited macrophages, together with the excited and proliferating T-helper cells, then produce a Type 4 delayed hypersensitivity reaction.
Cytotoxic Destruction
1.
A virus invades a cell in the gut.
2.
Viral envelope glycoproteins turn up on the invaded cell’s surface, presented in MHC-I complexes.
3.
A matching CD8+ cytotoxic T-cell wanders by, and realizes that the MHC-I cup contains its matching antigen. This stimulates it to divide into a clonal line of cells. (IL-2 from involved CD4+ helper T-cells is important in this process.)
4.
The clones of the cytotoxic T-cell go out to find cells with the right MHC-I and antigen pairing. When they find them, they secrete perforins to open the cells’ membranes and kill the infected cells.
Types of Cells Involved in the Immune Response
T-cells
T-cells carry “CD” surface markers. All T-cells are marked with CD2 and CD3. They proliferate, in general, when they encounter IL-2.
The helper cells (both Th1 and Th2) are marked with CD4 and CD28 molecules on their surface. They activate when their CD28 receptor binds the B7 surface marker on antigen-presenting cells. They are stimulated to divide and produce a clone line by IL-2.
Cytotoxic T-cells are CD8+. They are also stimulated by IL-2.
Regulatory T-cells are a subset of T-cells that moderate immune activation and maintain self-tolerance. (Previously, these cells were termed suppressor T-cells, but that was not an accurate reflection of what they do, so they were renamed.)
About 70 % of the body’s T-cells are helper cells. About 75 % of the circulating lymphocytes are T-cells (rather than B-cells, or other lymphocyte types).
Memory T-cells are formed, in addition to memory B-cells. (However memory B-cells get most of the attention, due to their impressive IgG response, when activated.)
T-cells mature in the thymus, and are selected for further development based on the response they have to self molecules. Those that react against self are deleted (die). The process is called “clonal deletion” and is also referred to as “negative selection.”
T-cells are also positively selected. This means that the T-cell must be able to interact with MHC proteins from the self. If they can’t, they won’t be able to facilitate the immune response, so they are also killed.
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