Harmful Immunity: A General Scheme.
So far we have been considering the successful
side of the immune system – its
defence role against microbial infection (bottom left). The effectiveness of
this is due to two main features: (i) the wide range of pathogens it can
specifically recognize and remember, and (ii) the strong non-specific
mechanisms it can mobilize to eliminate them.
Unfortunately, both of these
abilities can also operate against their possessor. 1 Wide-ranging specificity necessitates an efficient mechanism for
avoiding action against ‘self’ determinants (the problem of autoimmunity;
centre). Also there are cases where the elimination of non-self material may
not be desirable (the problem of transplant rejection; top). 2 Strong
non-specific weapons (e.g. complement, polymorphs, macrophages and other
inflammatory agents; centre) cannot always be trained precisely on the proper
target, but may spill over to damage neighbouring tissues (the problem of hypersensitivity:
right).
The
nomenclature of these immunopathological reactions
has never been very tidy. Originally, any evidence of altered reactivity
to an antigen following prior
contact was called ‘allergy’, while ‘hypersensitivity’ was defined as ‘acute’,
‘immediate’ or ‘delayed’ on the basis of the time taken for changes – often
quite harmless skin test reactions – to appear. In fact ‘harmful immunity’ can
arise as a result of inappropriate or excessive responses to foreign antigens
(innocuous ones as in many common allergies and allogeneic transplants or as a
by-product of the response to pathogens) or to self antigens (giving rise to
autoimmunity). In all these cases the basic mechanisms are often shared and can
be usefully classified according to the very influential scheme of Gell and
Coombs (extreme right). However, this classification only covers
hypersensitivities involving adaptive immunity, and it is becoming increasingly
clear that many of the most common degenerative diseases, such as
atherosclerosis and Alzheimer’s disease are caused by chronic activation of
innate immunity, especially macrophages, independently of adaptive immunity. A modified
classification that includes ‘innate hypersensitivities’ is therefore probably needed.
TH Helper T cell, which by the recognition of
carrier determinants permits antibody responses by B cells and the activation
of macro- phages. T cells recognizing self antigens probably exist in every
person but are normally kept in check by a variety of mechanisms (see Figs 22
and 38).
B B lymphocyte, the potential antibody-forming
cell. B lymphocytes that recognize many, although probably not all, ‘self’
determinants are found in normal animals; they can be switched on to make autoantibody
by ‘part-self’ (or ‘cross-reacting’) antigens if a helper T cell can recognize
a ‘non-self’ determinant on the same antigen (e.g. a drug or a virus; for
further details see Fig. 38).
T C Cytotoxic T cells against ‘self’ cells have
been demonstrated in some autoimmune diseases (e.g. Hashimoto’s thyroiditis).
Mast cell A tissue cell with basophilic granules
containing vasoactive amines, etc., which can be released following interaction
of antigen with passively acquired surface antibody (IgE), resulting in rapid
inflammation – local (‘allergy’) or systemic (‘anaphylaxis’) (see Fig. 35).
Complexes Combination with antigen is, of course, the
basis of all effects of
antibody. When there is excess formation of antibody – antigen complexes, some
of these settle out of the blood onto the walls of the blood vessels
(especially in the skin and kidneys). Tissue damage may then occur from the
activation of complement, PMN or platelets (see Fig. 36). Platelet aggregation
is a prominent feature of kidney graft rejection. Alternatively, antibodies can
form complexes with self antigens on the surface of cells (type II
hypersensitivity), activating complement and damaging tissue.
Complement is responsible for many of the tissue-damaging
effects of antigen - antibody interactions, as well as their useful function
against microorganisms. The inflammatory effects are mostly due to the
anaphylatoxins (C3a and C5a) which act on mast cells, while opsonization (by
C3b) and lysis (by C5–9) are important in the destruction of transplanted cells
and (via autoantibody) of autoantigens.
PMN Polymorphonuclear leucocytes are attracted
rapidly to sites of inflammation by complement-mediated chemotaxis, where they
phagocytose antigen–antibody complexes; their lysosomal enzymes can cause
tissue destruction, as in the classic Arthus reaction. Paradoxically, impaired
function of these cells such as occurs in chronic granulomatous disease and perhaps also Crohn’s
disease may lead to chronic
bacterial infections becoming established, which in turn lead to chronic
inflammation and tissue damage.
MAC Macrophages are important in phagocytosis, but
may also be attracted to and activated at the site of antigen persistence,
resulting in both tissue necrosis and granuloma formation (see Fig. 37). The
slower arrival of monocytes and macrophages in the skin following antigen
injection gave rise to the name ‘delayed hypersensitivity’. Bacterial
lipopolysaccharide (LPS) and several other microbial molecules can
activate macrophages directly, causing TNF and IL-1 release. When this occurs
on a large scale, it can result in vascular collapse and damage to several
organs. This ‘endotoxin shock’ (a type of hypersensitivity of ‘innate’
immunity) is a feature of infections with meningococci and other Gram-negative
bacteria (see Fig. 29). LPS can also directly activate the complement
(alternative) and clotting pathways. Macrophages can also be activated by some
non-infectious stimuli. Uric acid crystals activate macrophage IL-1 secretion
and give rise to the painful symptoms of gout. Chronic macrophage activation by
oxidized lipoproteins in blood vessels or the β amyloid protein in brain may
underly atherosclerosis and Alzheimer’s disease, respectively.
Types of hypersensitivity (Gell
and Coombs’ classification)
- Acute (allergic; anaphylactic; immediate; reaginic): mediated by IgE antibody together with mast cells (e.g. hay fever). Can also give rise to eosinophil activation, most notably in asthma.
- Antibody mediated (cytotoxic): mediated by IgG or IgM together with complement or phagocytic cells (e.g. blood transfusion reactions, rheumatic fever, many autoimmune diseases).
- Antigen–antibody complex mediated: inflammation involving complement, polymorphs, etc. (e.g. Arthus reaction, serum sickness, SLE, chronic glomerulonephritis).
- Cell mediated (delayed; tuberculin-type): T-cell dependent recruitment of macrophages, eosinophils, etc. (e.g. tuberculoid leprosy, schis- tosomal cirrhosis, viral skin rashes, skin graft rejection).
- Stimulatory: a proposal to split off from type II those cases where antibody directly stimulates a cell function (e.g. stimulation of the thyroid TSH receptor in thyrotoxicosis).
