The following points highlight the three main forms of adaptive immune response. The forms are: 1. Humoral Immune Response 2. Cellular Immune Response 3. The Complement System.
Form # 1. Humoral Immune Response:
It is during the fifth month of intrauterine life that immunoglobulin producing cells appear in the spleen and lymph nodes. Subsequently, both IgM and IgG are synthesised by the foetus with IgM predominant. Thus, B-cells begin their life as IgM producer. Hence, during the primary immune response B-cells secrete IgM antibody.
They later switch over to the synthesis of IgG antibody. It is during the development of some clones and even perhaps within the individual cells that this ‘switch’ event occurs from production of IgM to that of other immunoglobulin’s. This IgM-IgG ‘switch’ seems very likely to depend upon the influence of T-cell on the B-cell population.
When an antigen in either soluble or particulate form is introduced for the first time into a host, there is a rapid increase in synthesis of protein, in the cells of the lymphoid organs indicated by adherence of the antigen to B-cell receptors. This immune response takes 7-14 days and antibodies eventually can be detected in the blood at low levels and for a short duration.
This is called primary immune response. When the same antigen is introduced for the second time, there is slight fall of circulating antibody at that time due to rapid mopping up of antibody with the antigen. This can be detected by a fall in the level of antibody in the blood. After 1-2 days a marked rise in the level of antibody begins reaching a peak within 3-5 days.
This high level is maintained for a long period, even months. This is recognised as secondary immune response. The interval between primary and secondary antigenic stimulation should not be less than 10 days. The shorter interval will not only reduce the rise in antibody level, but may lead to tolerance. The longer interval allows the immune system to increase the number of antibody forming cells following second introduction of the same antigen.
Soluble antibodies (immunoglobulins) as components of serum proteins originate from B-cells via plasmablasts through plasma cells. The latter synthesize and secrete immunoglobulin’s. During primary immune response IgM is the first formed antibody in the serum. In the secondary immune response IgG is the usual predominant type of immunoglobulin and IgM is usually much less.
Form # 2. Cellular Immune Response:
In this response antigen is either fixed in the cells of the tissues or is a modified part of the body’ sown tissues cells. T-lymphocytes are sensitised by the antigens in the peripheral circulation since large number of circulating lymphocytes are T-cells. The T-cells that produce cell-mediated immune response, recirculate through the body.
About 90% of the cells go through the artery via the post-capillary venules and the efferent lymphatic’s of the lymph node to the thoracic duct or via the periarteriolar sheath to the marginal sinus of the white pulp of the spleen to the venous system back to the circulation. Only 10% of cells leave the capillaries of various parts of the body, moving through various tissue spaces into the lymphatic’s.
This is particularly important for the gut-associated lymphoid tissue. 70%-80% of T-cells participate in recirculation and this occurs about once in 24 hours. This continuous movement of T-cells ensures that antigens or microbes entering the body come in contact with specific reactive cells since all T- cells carry on their surface antibody-like receptors specific for the particular antigen.
These sensitised lymphocytes first differentiate into large cells within 4 days of sensitisation. Then they begin to divide into new subpopulations which go to other lymph nodes as immunologically active cells. Subsequently, the immunologically active cells are found in the peripheral blood.
The cellular immune response inhuman depends on intact thymus during foetal and neonatal life since it is in the thymus where primitive immunocytes differentiate and proliferate with the ability to induce immunological competence in the lymphocytes. The changes associated with this can be detected in murine animals as membrane antigens as Thy (theta), Th and Ly. Functional activity of the Ly marker can be defined as helper cell activity, cytoxic T-cell and suppressor T-cell (vide infra).
On second contact with the same antigen the sensitised T-cells are differentiated into several subpopulations. Some are able to secrete lymphokines. These consist of a variety of soluble mediators of cell-mediated immunity. These have effect on macrophages, lymphocytes and blood vessels.
The important ones are macrophage migration inhibition factor (MIF), macrophage activating factor (MAF), chemotactic factor (CF), mitogen factor (MF), skin reactive factor (SRF). Other T-cells are cytotoxic T-cells which take part in eradication of virus infected cells or bringing about the elimination of spontaneously rising neoplastic cells. Some other cells work as ‘memory’ T-cells and ‘helper’ cells or ‘suppressor’ cells for B lymphocytes in connection with humoral immune response.
The T-cell- B-cell co-operation is thought to be mediated through a soluble substance, T-cell factor, which mediates the interaction without direct contact with B-cell surface receptors. Some of the factors have no specificity for antigen and will promote all thymus dependent antibody responses. Other antigen specific factors strictly carry a binding site for antigen in one hand, and another binding site for the ‘acceptor’ site of B-cell to initiate them for immunoglobulin production.
In addition, the role of macrophages in the co-operation between T-cell and B-cell is required in connection with particular antigens like virus or bacteria or fungus, to process and present it correctly to T-cell and B-cell. These sensitised cells then proceed to interact in the follicles of the lymph node or white pulp of the spleen.
‘Suppressor’ T-cells, on the other hand, balance the immunological response from becoming excessive by interacting with ‘helper’ T-cells, T-cells releasing lymphokines and possibly with B-cells. Since the ‘suppressor’ T-cells specifically block immune response, they can only do so acting in direct competition with the ‘effector’ immunocytes for antigens or by producing soluble mediators as in case of ‘helper’ T-cells.
Thus, immunological unresponsiveness or tolerance can develop as a result of elimination of active clones of immunocytes or from an increase in the activity of these suppressor’ T-cells. Decline in the activity of ‘suppressor’ T-cells is accompanied by an increase in the production of various auto-antibodies and thus indicates the loss of self-tolerance.
Form # 3. The Complement System:
Complement was known as heat labile serum component. Complement is now known as a complex group of serum proteins. Its components interact with certain antigen antibody complex or microbial protein. This activates complement to initiate the primitive process of inflammation and phagocytosis.
The latter helps in termination of infection. Complement components are not all synthesised by a single type of cell, but the main sources of the components are the intestinal epithelia, macrophages, liver and spleen. Complement has nine factors or components (C1-C9), C3 being most abundant (1200 µg/ml).
The activation of complement fragments occurs by immune complexes formed by antigen, antibody (IgG or IgM) and participation of Fc fragment. During activation the cleavage of larger fragments occurs along with combination with other components while small fragments go to the body fluid. Moreover, the activation of complement occurs at cell surface in the vicinity of antibody molecule.
The first three components C1, C4 and C2 circulate in an inactive form as proenzymes. Component CI reacts with Fc fragment of Ig and after its interaction with antigen, the complement binding site is exposed. Subsequently, CI comprised of three distinct proteins (C1q, C1r and C1s) held together by calcium ion (Ca++) interacts. This may be regarded an initiation stage of the classical pathway.
C1 acts on C4 and C2 resulting in C42 complex (C3 convertase) and release of C2-kinin, a chemical mediator of inflammation. C42 (C3-convertase) activates C3 with release of C3a, anaphylotoxin, which releases histamine from mast cells and basophils. C3b attached to the cell surface, as in the case of microbes, helps in phagocytosis by macrophages and chemo taxis for neutrophils. It also releases platelet activating factor from platelets and helps inflammation while C3 inactivator regulates the release of C3b. Another pathway of activation of complement occurs with C1, C4 and C2, and also without Fc fragment of antibody.
This can be initiated by immunoglobulin (IgD, IgA or possibly IgE) and also by various polysaccharides including endotoxin, zymosan, and factor from cobra venom. Normally, zymosan reacts non-specifically with a protein called properidin (P) and a glycine rich glycoprotein called Factor B or C3 proactivator (C3PA) as well as C3 itself and the resulting complex inactivates C3.
Inactivation of C3 is associated with production of C3a and C3b in the serum. Those substances in the presence of magnesium ion convert C3 proactivator to C3 activator, which splits C3 into large C3b and small C3a. The factor B then binds with C3b to form a complex C3b, B. This acted on by factor D produces the active convertase complexC3bB which catalyses the conversion of C3 to C3bby the feedback circuit. C3b inactivator cleaves the C3b into two fragments (3c and 3d).
Membrane Attack Stage:
Following fixation C3b in association with its activating enzyme C3 convertase forms another enzyme, C5 convertase. The latter actson C5; a small subunit C5a, anotheranaphylotoxin, is split off. This is also a potent polymorph nuclear neutrophil chemotactic agent and is released into the body fluid. The larger C5b remains bound to C6 and C7 as the activating complex C5b67.
This has the property of chemotaxis for neutrophils. Finally, there is fixation of C8 and C9 with liberation of phospholipase leading to damage to the cell wall and its lysis. This is the basis of red cell lysis in complement fixation test. Some thin walled pathogens, e.g., trypanosomes and malaria parasites are killed by complement.
This is also observed with gram negative bacteria in association with lysozyme. Activation of complement system is controlled by the lability of the activated components, by esterase inhibitor and C3b inactivator.
Functions of complement are:
(i) Ability to kill various types of gram negative bacteria or virus after its interaction with antibody with their cell wall and making them susceptible to lysozymal action,
(ii) Helping destruction of tumour cells in the presence of antibody,
(iii) Chemotaxis for neutrophils at the site of antigen antibody interaction with the help of C567 complex,
(iv) Release of substance C3a or C5a known as anaphylotoxin, release of histamine and contraction of smooth muscle,
(v) Helping phagocytosis with the components of C1 and C3,
(vi) Formation of plasma kinin from C2 component and increase of permeability,
(vii) Action on platelets releasing platelet activating factor (PAF) and release of 5HT helping vascular changes and exudation in inflammation, and
(viii) Helping the destruction of cells by interaction with antigen-antibody complex on the surface membrane of the cell.