From: kja@cbnewsf.cb.att.com (krista.j.anderson)
Subject: Re: Allergy:  Several Questions and Inquiries
Summary: LONG - Should I have emailed it???
Organization: AT&T
Date: Fri, 18 Dec 1992 23:30:38 GMT

In article <1992Dec10.231824.6058@netcom.com>, noring@netcom.com (Jon Noring) writes:
> As an allergy sufferer, and one who is not trained in medicine, I would like
> to get a fairly simple, yet comprehensive explanation of the immunological
> processes involved with inhalant and food allergies.

You asked a big question.  I'm not an immunologist, but will try to
answer based on what I've read, especially since I promised to
write a FAQ on this subject for sci.med anyway.  I can never figure
out how to explain something unless I begin at the beginning, so
bear with me.

A. Immune system genes - There is whole lot I don't know about the
genes involved with the immune system.  However, it's good to at
least know that there is a Major Histocompatability Complex (MHC)
group of genes that determine the Human Leukocyte Antigen (HLA)
which is the set of proteins on body cell membranes that mark
the cells as self.  Certain classes of HLA especially mark
particular leukocytes (white blood cells), other classes mark
complement proteins.

B. Defenses against antigens such as viruses, bacteria, etc.
   1. mucous - Mucous in the nose, throat, lungs and digestive tract
can trap invaders.  There is also IgA antibody in and around the
mucous membranes and this will attach to antigens and then the 
antibody/antigen complex may get trapped in the mucous and the whole
thing sneezed, coughed, spit, vomited or excreted out.  Mucous can
also help get rid of inert particles like dirt or smoke.

   2. macrophages - I saw a picture of one of these critters in a
book and it was reaching out a long "arm" to encircle an invading
microorganism.  It seemed almost to have a life of its own and I
wondered if these white blood cells are somehow driven to eat
microorganisms for their own survival somehow.  Ever since, I've
felt a bit like a colony of creatures instead of a single entity.
      I also saw a photo of a macrophage locked hopelessly forever
with an asbestos fiber, which of course would never be digested.
The book with photos was _The Incredible Machine_.
      Neutrophils are smaller white blood cells that also kill
invaders by phagocytosis.  In both cells, the microorganism or
debris is engulfed by the phagocyte and encased in a phagosome
chamber to isolate it from the cell's own cytoplasm.  Then lysosome
granules fuse with the phagosome and release over 60 types of
digestive enzymes into it.  The organism is generally killed within
minutes, but some bacteria have evolved a coating that survives
within the phagolysosome where they can reproduce.
      Over the next few hours the organism or debris is digested.
Waste products, as in any cell, are dumped into the blood for
filtering through the kidneys and so on. 
      A macrophage will eat about 100 microorganisms in its
lifetime which may be months or years, a neutrophil, about 25.
Neutrophils are more numerous, I think, and are the major component
of pus. 
      After the macrophage has finished its "meal" it presents to a
T cell some of the invader's antigenic protein on the outside of its
cell membrane along with its own HLA antigen.
      The antigen-presenting macrophage secretes cytokines which
activate T cells.  It also secretes chemotaxins to attract other
leukocytes such as neutrophils and monocytes.  Monocytes from the
bloodstream mature into macrophages when they reach the tissue of
their destination and then stay there.
      Macrophages also secrete H2O2 and other oxygen metabolites
that can help destroy tumor cells.
      The ways that a macrophage stays close to an invader are
electrostatic charge or opsonization by having receptors for Fc
chains of antibodies whose other ends are bound to antigen.

   3. T cells - Helper T cells are activated by the cytokine of the
antigen-presenting macrophages.  These in turn activate killer T
cells and trigger increased reproduction of B cells and their
differentiation into antibody-producing plasma cells.
      Killer T cells as well as natural killer cells (aka null
cells) use toxic proteins (e.g. cytolysin, perforin) to destroy body
cells that are infected with viruses.  Natural killer cells also
destroy tumor cells. 
      When an infection has subsided, supressor T cells halt
reproduction of B cells and deactivate the killer cells.  Memory T
cells and memory B cells are left after the initial infection and
these are specific for the particular antigen.  An initial infection
can require up to 7 days for plasma cells to build up a measurable
level of antibodies; subsequent infections cause memory T and memory
B cells to build up antibodies to that level within hours.
      Antigen-presenting macrophages also secrete interleukin-1
and gamma interferon.  These two chemicals cause fever and malaise.
Heat from the fever may aid phagocytosis. 

   5. antibodies - Just how it is that antibodies for thousands of
antigens come to exist in the body is still a subject for study.
Although there is the germ theory that a person is born with them,
the more popular somatic mutation theory is that they are produced
only in response to the presence of their matching antigen.  I don't
know the exact mechanism, but immunologists probably have ideas.
      The first antibody produced is immunoglobulin M (IgM) which is
much like IgG (gamma globulin) except that it has 5 times the
antigen binding sites.  IgG is a set of protein chains with
disulfide bonds between them and looks like a Y-shape, with the
bottom fraction being an Fc part that can bind to phagocytes and
the top parts of the Y being 2 antigen binding sites (Fab); IgM has
10 such sites, but only 5 can really be used.  Next the plasma
cells make IgG which comprises 75% of the antibodies.  IgG can
cross the placenta to give temporary immunity to a fetus.  IgG can
neutralize bacterial endotoxins as well as bacteria themselves.
      IgA is in mucous, saliva, tears, semen, urine, colostrum,
milk and blood serum.  The function of IgD is only hypothesized at
this time.  IgE is the antibody involved in allergic reactions.
      Antigens are usually proteins and must be 10,000 daltons or
larger in order to trigger antibody production (I think; allergens
must be large in order to bind with more than 1 IgE on a mast
cell).  However, smaller molecules may bind with a protein in the
body to form a hapten that can also trigger the allergic (or immune?)
response.
      IgG1  attaches to most bacteria antigens
      IgG2  attaches to sugar-coated bacteria
      IgG3  attaches to free floating viruses
      IgG4  dilates blood vessels
I don't know exactly how antibodies attach to antigens.  I've been
assuming that it's a chemical bond, but it may be adhesion or some
other means?
      Ok, so we've got macrophages presenting antigen, helper T
cells and B cells activated and plasma cells making about 300
antibodies per second.  What happens next is the complement
cascade.  This is a chain of events with the last step being an
explosive chemical reaction that blows up the invading cell.  It is
discussed in more detail below.  Also note that antibodies can bind
to other things besides invading cells, such as toxins.
      One more note about lymphokines and monokines, collectively
called cytokines, of which there are more than 50, is that
interferons secreted by T cells and macrophages can also be produced
by other body cells and (1) induce infected body cells to make
enzymes to break down their own mRNA, (2) make kinase which inhibits
mRNA synthesis, and (3) prevent assembly of viral parts.
Neighboring cells are then stimulated to also make interferon with
the same results.
      I think interferon is also used to control cancerous cells.
      A cancer treatment being used is to remove leukocytes, treat
them with extra interleukin-2 and then reinject them.  This
activates more T cells and natural killer cells.

   6. other leukocytes - In addition to the cells mentioned, there
are eosinophils, basophils and mast cells, all mentioned below.
      
C. Allergic reaction
   1. mast cells and basophils and mediators - Basophils are like
mast cells, but are smaller, having about 20% (100) of the granules
that mast cells have (500) and are present inside the blood stream
whereas mast cells are most numerous in the lungs, connective
tissues, uterus and around blood vessels.  What I say about mast
cells applies also to basophils.
      IgE and eosinophils are thought to be for the purpose of
fighting off worms and big parasites like that, but for reasons that
are unclear fight off pollens and other allergens also.  There are
hypotheses that atopic people have excessive IgE and eosinophils
and there are other hypotheses that atopic people have insufficient
suppressor T cells to inhibit a reaction to what should be
considered inert proteins and haptens.
      In any case, some particular HLA components have been
correlated with some allergies (e.g. ragweed) and intolerances
(e.g. celiac) as well as other immune disorders.
      IgE accounts for only .002% of the antibodies in normal
people, but atopic people may have 10 times as much and people with
worms may have 20 times as much.
      IgE's Fc part attaches to mast cells, which have about 500,000
receptor sites for them, and the Fab parts attach to allergens.
When 2 IgE's on the surface of a mast cell are both complexed with
a single allergen, it changes the cell membrane, the cell
collapses, releasing granules of histamine and other mediators.
The cell membrane itself, upon exposure to certain enzymes, forms
still other mediators, such as prostaglandins, thromboxanes and
leukotrienes. 
      The IgE's change the cell's energy transfer resulting in an
influx of Ca++ which triggers release of the granules and also
triggers synthesis of the mediators formed from the cell membrane,
or really, from some fatty acids in the cell membranes, either
arachidonic acid or eicosapentaenoic acid.  Since the former
results from omega-6 linoleic acid, whereas the latter results from
omega-3 linolenic acid, the precise nature of the prostaglandins
and thromboxanes may depend on what you eat, with the omega-6
derivatives leading to more inflammatory mediators than the omega-3.
      While the effects of eating omega-3 fish or flax oils instead
of other oils or fats are not thought to give dramatic changes, some
books on rheumatoid arthritis have gone as far as to recommend the
omega-3 oils, in say, cold water fish 3 times a week, in hopes of a
slight effect.  Omega-3 oils are also present in canola oil,
soybean oil, walnuts and in small amounts in other foods.
      Histamine is probably the most noticeable mediator.  It causes
itching, and dilates blood vessels, allowing fluid as well as
blood cells to enter the area of allergic activity, and causing
redness and swelling.  It also causes smooth muscle contractions.
      Prostaglandins seem to have a regulatory function, and can
cause asthma when disrupted.
      Macrophages also have IgE receptors and can release
arachidonic acid which is then converted to other things.
      One of the mediators released in the mast cell granules is
Neutrophil Chemotactic Factor of Anaphylaxis which attracts
neutrophils capable of releasing arachidonic acid, thromboxane A2
and some enzymes.
   2. Eosinophils - Eosinophil Chemotactic Factor of Anaphylaxis 
draws eosinophils, the heavy guns of anti-worm warfare.  They
secrete substances that are highly toxic to nematodes and
trypanosomes, but also to any body cells that get in the way.  They
also release other substances and can damage epithelial tissue of
the lungs.  Damage can also occur in the digestive tract, skin and
possibly joints.
    3. Other chemicals - Other chemicals released during allergic
reactions are heparin, which increases blood flow, Platelet
Activating Factor, which leads to release of vasoactive amines,
serotonin, which has no role in atopic reactions, leukotrienes,
which can cause bronchoconstrictions, and bradykinin, which is a
vasodilator and smooth muscle constrictor and also widens arteries
lowering blood pressure, and stimulates nerve endings to cause pain.
      There are several types of prostaglandins and thromboxanes;
they seem to have regulatory functions.  Some are bronchodilators,
others bronchoconstrictors; some are vasoconstrictors, others
vasodilators.

D. Complement cascade and chemicals - The complement cascade is
usually initiated by complexed IgG or IgM.  However, there is an
alternative pathway that can be initiated by a large quantity of
carbohydrate, for example, in a large collection of IgE, which has
carbohydrate in its structure.  And, the complement cascade includes
some chemicals that can cause mast cells to disintegrate and release
their granules, so infections and allergies have some similar
symptoms. 
    Below, the things starting with C are complement proteins and
this is how it is presented in reference 1.  (I think the
alternative pathway comes in at stage 5?)

Stage 1
    a. Antibody and antigen bind to form complex
    b. C1q binds to the Fc part of the antibody
    c. C1r and C1s bind to C1q in the presence of Ca++
Stage 2
    a. C1s acts as enzyme on C4, cutting it into C4a and C4b
       C4b attaches to complex, C4a is released into blood
    b. if the antigen indicates viruses, they are neutralized
    c. C4a acts as anaphylatoxin to disintegrate mast cells and
       cause eosinophils to release their chemicals
       (this results in vasodilation and smooth muscle contraction,
       possibly bronchoconstriction)
Stage 3
    a. C1s cuts C2 into C2a and C2b in the presence of Mg++
       the reaction releases kinin which contracts smooth muscle and
           increases blood vessel permeability
       C2a attaches to C4b; C2b is released into blood
Stage 4
    a. C4b,2a acts as enxzyme on C3
Stage 5
    a. C3b complexes with C4b,2a to form C4b,2a,3b
       C3b binds to neutrophils and macrophages
    b. C3a, released to blood, is a potent anaphylatoxin
Stage 6
    a. C4b,2a,3b cuts C5
       C5b, when complexed, can inactivate bacterial endotoxin
    b. C5a, released to blood, is potent anaphylatoxin and
       chemotaxin, attracting eosinophils, neutrophils and macrophages
Stage 7
    a. C5b binds C6 and C7 to make C5b,6,7
Stage 8
    a. With C5b,6,7, C8 and C9 attached to the complex, C8 destroys
       the invading cell protein via cytolysis

E. Other ways that mast cells can be disintegrated are from
histamine-releasing foods such as egg white, shellfish,
strawberries, tomatoes, fish, pork, chocolate, pineapple, papaya
and alcoholic beverages, lectins in under-cooked legumes or wheat
germ, or certain drugs, maybe.
   Asthma attacks can be brought on or aggravated by infections,
exercise, cold air, fumes and odors, smoke, changes in barametric
pressure.

F. Hypersensitivity types
   1. Type I hypersensitivity is the atopic response with IgE
described above.

   2. Type II hypersensitivity, also called cytotoxic
hypersensitivity, is a problem where IgG and/or IgM antibody binds
to surface proteins, carbohydrates or haptens associated with
self-cells.

   3. Type III hypersensitivity is an inflammation caused by a
deposit of antigen/antibody complexes.  If the number of antibodies
far outweighs the number of antigens, then the complex precipitates
out too fast and settles into surrounding tissue.  If the antigens
far outweigh the antibodies, then the complex is too soluble and
travels through the bloodstream until it is deposited in tissue at
another site.  In either case, the complexes attract macrophages
and other lymphocytes as well as complement proteins, and the
chemicals cause the inflammation as well as tissue damage.

Some books say that celiac disease (gluten intolerance) as well as
cow's milk protein intolerance suggests Type III hypersensitivity.
It says a Type I IgE response may increase permeability of
intestinal walls, so that complexes of food protein and antibody
settle into the microvilli, which get destroyed by the immune
response.

There are also some substances called lectins that bind with body
cells and cause them to agglutinate, so it is hypothesized that in
some people, gluten acts as a lectin.  Lectins can also cause mast
cells to release their granules, or they can prevent them from
doing so. 

   4. Type IV hypersensitivity is also known as delayed or
cell-mediated hypersensitivity and its best known example is poison
ivy.  Normally, macrophages engulf and digest invaders and then
attach the invaders' antigenic proteins on their own cell surfaces
along with HLA.  Then they present the antigen+HLA to T cells and
the T cells are supposed to become activated and activate B cells
(which make antibodies) in turn.

In Type IV, when macrophages present antigens+HLA to T cells,
instead of just becoming activated, the T cells bond with the
complexes.  This causes the T cells to release tissue-damaging
lysozyme as well as lymphokines which stimulate more macrophages.
Tuberculosis works this way.  Intolerance of thimersol in contact
lens solutions is also a Type IV.

REFERENCES
1. Joneja, Janic Vickerstaff and Bielory, Leonard, _Understanding
   Allergy, Sensitivity & Immunity_, NJ: Rutgers University Press, 1990.
2. Brostoff, Jonathan and Challacombe, Stephen J., London: Bailliere
   Tindall, 1987.
3. Dwyer, John M., _The Body at War_, NY: NAL Books, 1989.
4. Nurse's Reference Library, _Diseases_, PA:Springhouse Corp, 1987.
5. Mizel, Steven B. and   Jaret, Peter, _In Self-Defense_, US: Harcourt
   Brace Jovanovich, Publishers, 1985.
6. _Genetics_
7. _The Incredible Machine_, Wash DC: National Geographic Society,
   1986.

> Jon Noring
> Charter Member #000001 of the INFJ Club.

Well, I'm an INTP, myself.  Found out 'cuz I didn't want to go to a
cocktail party and be the only one not to know their type.  :-)
-- 
Krista Anderson, krista@ihlpf.att.com  or  ihlpf!krista@att.att.com
I don't want to be here; I want to be in an Agatha Christie novel,
or in a musical, like Mary Poppins.
Newsgroups: bionet.immunology