The Human Immune Response

(Updated 8 March 2004) 
 

Remember: the information here is so oversimplified that it is not quite true. But it does give you a sense of how thing work.

Antibody diversity

  • We have about 1 trillion different cell that can each recognize a different thing
    • the diversity pre-exists and does not require prior exposure
    • there are not too many copies of each such cell
  • there are several classes of cell for each recognition specificity
    • e.g antibody producers, killer cells, and regulatory cells

Origin of antibody diversity

  • relatively small number of modules that can be shuffled
    • how many different bridge hands can you deal with a 52 card deck?
  • Once the diversity is established (the hand is dealt) the cell is mature and its identity is defined forever

Two basic cells of immunity

  • Macrophages (=Big eaters)
    • and their relatives
    • we’ll pretend that macrophages are the only members of the family
  • Lymphocytes (lymph cells)
    • T lymphocytes (T cells)
    • B Lymphocytes (B cells)

What the cells types do

  • Macrophages eat things
  • B cells make antibodies in the bloodstream
  • T cells tell others what to do (some also kill things)
  • B cells and T cells generate a diversity like antibody diversity

The rules for self/non-self

  • Positive selection
    • if a “self” molecule recognized, suicide early in development
  • Negative selection
    • if “self-recognizer” matures, suppressor cells block its action until it dies of old age.

What happens when cells of the immune response meet antigens?

  • An empty antigen presenting molecule (MHC) on the surface
    • Ignore it
  • An antibody-antigen complex
    • Eat it or kill it if you can recognize it
  • An MHC filled with an antigen on the surface
    • Tell it to multiply like crazy

How Does it Work?

Antigen presentation

A macrophage is just a special kind of phagocyte

When a macrophage encounters a bacterium or virus

  • It engulfs it in a vessicle (pagocytosis — remember that from Salmonella and typhoid?)
  • It fuses the vessicle with a lysosome and digests the virus to small pieces
  • It puts an MHC molecule (antigen-presenting molecule) into the membrane
    • This has a non-specific holder (the little square in the picture) that will grab almost any piece of any molecule
    • The result is a combination of MHC and a piece of the virus
  • Phagocytosis happen in reverse to put the bound antigen on the surface of the cell

The macrophage helps the immune response work

  • It destroys the invader (e.g. virus) — after all, it is a phagocyte
  • It carries the antigens derived form the virus to the lymph nodes where lots of immune cells can see them
  • It carries multiple copies of the antigens from a single virus so several different cells can bind and be kept very close to each other
  • The MHC (antigen-presenting) molecule gives T4H cells (see below) a second thing to bind to — increading the time the T4H cells stays attached to an antigen.
    • the CD4 molecule binds to the MHC
    • otherwise the interaction between CD4 and antigen would be to weak to hold — remember, always need 2-point attachment for strength and stability
      • that’s why CD4 is so vital to the immune response
      • that’s why HIV is so clever in using CD4 as its receptor.

The role of antigen presentation is to keep everything close together

  • In theory it could work without antigen presenting cells
  • but it would be hundreds of fold less effective
  • and it would be hundreds of fold less specific

Analogy of the perfume and the classroom

  • A person handcuffed to the one wearing strong perfume will surely respond (positively or negatively)
  • A person who comes near during change of class would be influenced, but only transiently
  • A person who did not happen to be near would sense little or no perfume
    • But theoretically, it is there, just very diluted
    • You don’t smell much of a New Yorker’s perfume in San Francisco, but in theory, it is everywher on the earth

Part I: B cells and “humoral immunity”

How to make the right antibody

  • B cells pre-exist with lots of different specificities
  • billions to trillions of possible kinds, but only thousands of each kind

Antigen bumps into a “wrong” B cell

  • nothing happens

Antigen bumps into a “right” B cell

  • If a T helper cell also comes along,
    • Those few cells start to make antibodies and secrete them into the blood
    • Those same cells start dividing like mad
  • If no helper cell, not much happens

T helper cells (CD4 or T4H cells)

  • Phagocyte (Macrophage) with antigen on surface are called “antigen presenting cells”
  • Bump into a “wrong” T4 helper cell or B cell:
    • nothing happens
  • Bump into a “right” T4 helper cell or B cell
    • T4 cells and B cells start dividing

The Net Result: “Clonal Expansion”

  • Instead of having a few T cells and B cells that are specific for that antigen, there are hundreds of thousands
  • All of those are secreting antibody against that antigen
  • Some of them go into a special state (“memory cells”) that can be re-activated without all that rigamarole
  • NOTE: antigen presenting cells have room to bind both T4H and B cells to the same cell
    • that brings them very close
    • signals from the T4H cell really work on the B cell

Cell-mediated Immunity

T-cells are Specific too

  • Make the equivalent of antibodies
  • but they stay bound to cell surface
  • Clonal Expansion works here too
  • T4H cells (CD4 cells) secrete growth factors when stimulated
  • Antigen presenting cells help by keeping the T4H cell bound longer
    • affinity for the MHC molecule AND the antigen — twice the binding strength,
    • lasts long enough to cause clonal expansion.

Macrophages not specific

  • Antigen bumps into a macrophage
    • macrophage ingests it and digests it to small pieces especially if coated with antibody
    • small pieces are “presented” on the surface
  • Macrophages are constantly grazing
    • vacuum cleaners of the blood and lymph
    • antigen presentation

Antigen-presenting macrophage bumps into a T4H-cell

  • Bumps into a cell with “wrong” specificity
    • nothing happens
  • Bumps into a cell with “right” specificity
    • T-cell makes the macrophage very aggressive in eating things
    • secretes attractants for more macrophages to come to the site
    • makes the T-cell proliferate too (clonal expansion)

TK cells (cytotoxic) also respond to signals

  • CD8 cells (=T8 or cytotoxic lymphocyte cells) kill other cells that have right antigens
  • T4H cells stimulate clonal expansion of TK cells too
  • Even T4H cells respond to signals
  • The signals that T4H cells use to tell B cells or macrophages to divide and multiply also affect themselves, causing clonal expansion here too
  • As a result, the probability that an antigen-presenting macrophage or B cell will find a “right” T cell is greatly increased and the whole system amplifies itself

But remember:

  • Your own special Antigen without antigen presentation
    • eat it or kill it (macrophage, or TK cells)
  • Antigen presentation without your own special antigen
    • ignore it
  • antigen presentation of your special antigen
    • divide and make lots more cells like yourself to recognize special antigen (T4H mediated signal)
    • or eat aggressively
  • The whole amplification depends on T4H cells

Where does this all happen?

  • Can happen in the blood (probably)
  • Lots happens in the lymph nodes
    • A strong filtration system
    • All antigens and cells get pulled into close contact here
    • Most of the immune systems cells are located here

There is a nice pictorial version of this on the website maintained by the Cancer Research Institute.

HIV attacks macrophages, dendtitic cells, and T4H cells (“M-tropic”)

  • Binds to CD4 and CCR-5
  • eludes destruction and antigen presentation
  • gets to nucleus and integrates
  • gets to lymph nodes and spreads
  • Dendritic cells are antigen presenting cells like macrophages
    • but they present the whole virus, not digested pieces
  • as a result they are the real “Trojan Horses” that can carry HIV to the lymph nodes where it can do the most damage

Later starts prefering T4H cells to macrophages and uses CXCR4 as co-receptor instead of CCR5

  • We don’t understand either of these facts

Tropism changes from M to T

  • Early (Primary infection) virus uses CD4 plus CCR5
  • do not require high amounts of CD4
  • Later virus uses CD4 and CXCR4
  • require higher amounts of CD4
  • We don’t know why they switch
  • Once T4 helper cells (CD4) go, the whole ability to amplify the system is lost