The ANSWERS problem Early, loosely targetted* Later, precisely |b Innate non-specific defences targetted immune defences B |l U<.a.|o.......MACROPHAGES G t |o <.a........CYTOLYTIC cell-mediated S<.t.|d.......NEUTROPHILS & EOs t T LYMPHOCYTES a | t I .c.|v.......COMPLEMENT PROTEINS a N k |e <.c........ANTIBODIES humoral ...|s.......NATURAL KILLER CELLS k from plasma cells M |s (originally B lymphocytes) Y |e |l C |_wall & other BARRIERS to the chemical & cellular attack on the T bugs are overcome by inflammation and its events, such as the release of MAST-CELL and other mediators. OUTCOMES MEANS Me intact: recognised as self and not to be attacked. Chemical protections: on cell surface; neutralisers for destructive enzymes; antioxidant mechanisms Bugs gone: cells phagocytose & digest bugs; antibodies counter their toxicity & make them more eatable; superoxide & other O2-based radicals attack them; defensive cells release other antimicrobial chemicals, e.g, defensins, major basic protein, cytokines; liver hepatocytes make acute-phase proteins to circulate for more chemical defence Infected cells: pores created in cell membrane; apoptosis/suicide gone triggered Bugs made unwelcome next time: circulating memory B & T lymphocytes with specific surface antibodies or T-cell receptors (TCR) for that kind of bugPrecise targetting is made possible by the prior proliferation of billions of B & T lymphocytes, accompanied by the generation of diversity in the antibody or TCR. The diversity is immense, covering all the possible molecular forms that might show up and injure one. Controlled mutation and rejoining of DNA (V & J regions) of the Ab or TCR genes produce the variety.
The initially crude targetting* of the innate or primitive system is refined
and made more effective by the evolutionarily more recent lymphocyte-based
immune system, which, in its turn, receives directions from the innate system.
Primitive animals had too few cells for the strategy of winning the anti-microbial lottery by buying all the tickets - making an Ab and TCR for every possible Ag.
Why keep two systems? The specific immune takes days to get going after a new antigenic encounter, because of the need to recruit cells and greatly amplify their number.
The above Fig. and text are in colour at Powerpoint.
Fig. 10 Immune responses: cell-mediated & humoral
_ Antigen-presenting presents Ag to the T | cell APC-Ag Lymphocyte | LYMPH / . | NODES activation/ . | recruitment/ helper | SPLEEN / . | / action. | TONSILS T B | Lymphocyte Lymphocyte | GUT | | | | | | | Plasma cell | | | _| | | | | - - - - - - - - - - - - - - - | - - - - - - - | - - - B | | L | | CM O | | |Complement O | | | |activation D | | | | - - - | - - - - - - - - - - - - | - - - - - - - - - - | - | - .- - | mast cell activation | | | . Mast-cell T | . | |. .| . activation I | chemotaxis . | | | S |. . . . . . . . . . . | Ig CM S | . T Ag U Macrophage. . . . . . . . Lymphocyte IMMUNE COMPLEX E Ag activation . S . direct lysis . Ig also boosts NEUTROPHIL Ag. . migration & phagocytosis of immune complexes |________CELL-MEDIATED RESPONSE_________| |______HUMORAL RESPONSE____________4 Immunologically competent cells - T & B lymphocytes and plasma cells - show an exquisite specificity to an individual kind of alien body, e.g., polio virus rather than smallpox, in binding themselves (by the T-cell receptor), or in their humoral product - immunoglobulins/ antibodies.
5 Sources of antigen, actual or potential, are:
.. (a) viruses and microorganisms;
.. (b) venoms;
.. (c) inspired particles, e.g., fungi, pollen, dander;
.. (d) foods;
.. (e) semen;
.. (f) the embryo;
.. (g) transplanted tissues, e.g., skin;
.. (h) altered autologous (own) cells, e.g., tumour products
.. (i) some medicaments, e.g., penicillin.
1 Plasma cells (immunologically competent)
l Develop from B lymphocytes (see 2.l below for B and T lymphocyte definitions) via a transitional cell involved in rearranging its immunoglobulin genes for expression, first for the cell-surface, then for secretion.
2 Synthesize and release specific humoral antibodies (immunoglobulins), after engagement with the presented antigens, and stimulations from helper T lymphocytes.
.. (a) bind and inactive the antigenic bodies;
.. (b) neutralize toxins;
.. (c) enhance phagocytosis;
.. (d) trigger the activation of special blood proteins - complement factors - which amplify the immune response.
4 Complement also binds to the antigen, potentiating the action of the bound antibody, and itself has lytic, signalling, and other effects. The three-part entity - antigen, antibody and complement - is an immune complex.
2 Lymphocytes (competent)
l Start as stem cells of fetal haemopoietic tissue, but fall into two classes differing in where they were conditioned for distinct tasks.
3 Roles of the T lymphocyte
5 Lymphocytes are classified by the reaction of certain of their surface
glycoproteins to monoclonal antibodies. Thus, inducer/helpers are CD4+;
cytolytic lymphocytes are CD8+; natural killer cells are CD3-, CD16+, CD56+;
B lymphocytes are CD19+, etc.
CD means Cluster-of-Differentiation antigens, and stems from the patterns of response of differentiating leucocytes to a great variety of monoclonal antibodies. It turns out that many kinds of cell aside from leucocytes express one or more of the antigens that the CD antibodies mark. These antigens only incidentally help characterize cells (e.g., marrow stem cells are CD34+), since they are working molecules - in adhesion and signalling, as enzymes, protective agents, etc.
6 Some T and B cells, having participated in an immune response to a
certain antigen, patrol the body as long-lived memory cells ready to
initiate an early and stronger secondary response, should the same antigen
intrude again - the basis of vaccination.
7 The distinction between self- and non-self-recognition, and the acquisition of memory by lymphocytes, may be confounded by presentation of the antigen in high doses, by unusual routes, or in immaturity just after birth. The confused lymphocytes that result remember to tolerate an antigen, to which they should react. This tolerance is believed to be a byproduct of a normal mechanism, whereby all normal cells are telling circulating T lymphocytes, with receptors for the normal cells' materials, not to react, but to die.
3 Dendritic antigen-presenting cells (APCs) and Macrophages (accessory)
1 APCs and macrophages/MØs concentrate some antigenic fragments on their surface, presenting them in a form more potent for stimulating lymphocytes.
2 What is presented on the surface is a small peptide, derived by degradation from the antigen, bound to a histocompatibility protein (MHC class I or II depending on whether the antigen is of intracellular (self) or foreign/exogenous origin). Intracellular antigens presented in this way include materials that viruses have forced the cell to make.
A non-sequitur: antigen-presentation is not limited to MØs and antigen-presenting cells. For example, B lymphocytes present antigen to T lymphocytes.
3 Once activated by a particular antigen, lymphocytes and macrophages exchange cytokine messages to:
.. (a) recruit more macrophages from the circulating monocytes;
.. (b) inhibit macrophage migration to keep macrophages at hand;
.. (c) activate macrophages to attack more vigorously the antigen by which the lymphocyte is activated, e.g., tuberculosis bacilli.
(These cytokines convey simple 'doggy' orders: Come! Stay! Attack!)
4 Macrophages phagocytose toxins and cells killed by other immune actions, and make cytokine factors, e.g., chemotactic for neutrophils.
5 Macrophages and other phagocytes liberate destructive enzymes and oxygen metabolites to lyse cells. They also digest matrix, e.g., by MØ elastase, so that they themselves may move more freely. Enzymes may also be regurgitated in phagocytosis, or be spilled after death of the cell.
To reduce the damage to surrounding tissues, extra-cellular degradative enzymes normally are neutralized by protease inhibitors in the plasma and tissues, such as alpha l-antitrypsin.
6 'Tingible-body' macrophages are in germinal centres. Their darkly stained (tingible) inclusion material is nuclear debris of apoptotic B lymphocytes that were selected against for not improving their affinity for antigen fast enough.
4 Granular leucocytes
l Neutrophils respond in strength to certain bacterial and fungal infections, avidly ingesting, say, streptococci, dying, and often accumulating to become pus.
2 Neutrophils and eosinophils are attracted to immune complexes which they phagocytose, but the materials that they use to attack microbes and parasites also damage tissues, e.g., airway epithelium in allergies.
5 Mast cells
l One kind of immunoglobulin (Ig) is already bound to their surface. Antigen entering the tissue bridges these IgE molecules, triggering the release of
2 histamine, which dilates vessels, increases their permeability and facilitates the exit of granular leucocytes, monocytes, antibodies, etc.
3 Heparin may hold histamine and other factors ready for discharge; if released itself, it might, as a polyanion, bind and neutralize toxins. Among the many other mediators are bradykinin and factors attracting granulocytes - chemokines.
4 The mast cell's reaction is an immediate hypersensitive one: the basis of allergies. An anaphylactic hypersensitive response in the airway lining is life-threatening, by overconstricting smooth muscle, and other effects.
Transplantation has wide use in the experimental approaches of Chapter 30.
l Most tissues can be grafted autologously to another site in the same individual, where they will live, if they can soon gain a new blood supply by revascularization by, or anastomosis with, the vessels of the host bed.
2 Transplants between two individuals will take - not be rejected - if they are isogeneic/syngeneic, and thus have identical tissue proteins synthesized according to the same DNA, e.g., in identical twins, or animals of the same sex whose forebears have been many times inbred.
3 Transplants between genetically different individuals can be:
.. (a) allogeneic/homologous between members of the same species;
.. (b) xenogeneic/heterologous between members of different species or orders.
The grafted tissue is antigenic and evokes the delayed T cell-mediated immune response.
4 An allogeneic graft made to a neonatal host can induce a permanent tolerance for that graft and subsequent grafts of the same tissue. The host, now composed of tissues differing genetically, has been made a chimaera.
5 Certain sites for allogeneic grafts slow down or prevent the antigen from draining to lymphoid tissue and eliciting an immune response. Such immunologically privileged sites are the cornea and brain.
6 Immunity depends on the proliferation and synthesis by cells. To help a graft to take, the response could be inhibited for a while by provoking apoptosis in the competent cells, or hindering their proliferation, with irradiation with X-rays, or with cytotoxic drugs or glucocorticoids. Transplant surgeons can also use agents, e.g., cyclosporin, to block the activation of T cells.
Sometimes the mechanisms of restraint against attacking one's own materials go awry. Clinically significant autoimmune targets include: gastric parietal cells, renal mesangial cells, pancreatic beta cells, thyroid follicular cells, skeletal muscle, myelin components, and basement membranes.