The Antigen

  

Acquired immune responses arise as a result of exposure to foreign stimuli. The compound that evokes the response is referred to either as “antigen” or as “immunogen.” An antigen is any agent capable of binding specifically to components of the immune response such as lymphocytes and antibodies. An immunogen is any agent capable of inducing an immune response. As a general rule: All immunogens are antigens but not all antigens are immunogens.

Characteristics of an immunogen

1. Foreignness – any substance that is foreign or not recognized by the body exhibits foreignness. However, a condition known as autoimmunity recognizes anything inherent to the body as foreign.

2. High molecular weight – molecular weight is the size of the molecule of a particular compound. To be immunogenic, it should have a molecular weight of more than 6000 Da (Daltons).

3. Chemical complexity – immunogens are usually protein in nature and protein are diverse in number. A combination of different types of protein to form a high molecular weight compound is an essential characteristic to be immunogenic. It is also important to note the levels of structure of the protein to be immunogenic.

A hapten is a compound of low molecular weight that is not itself immunogenic but that, after conjugation to a carrier – protein or cells becomes immunogenic and induces antibody, which can bind the hapten alone in the absence of carrier.

4. Degradability – in order for most antigens to stimulate immune responses (B or T cell mediated), interactions between antigen–presenting cells (APC) and helper T cells must occur. APCs must first degrade the antigens through a process known as antigen processing (enzymatic degradation of antigen) before they can express antigenic epitopes on their surface and stimulate antigen – specific helper T cells. The antigen–presenting cells have structure referred to as major histocompatibility complex (MHC) proteins to which “processed” fragments of the protein can bind noncovalently. This complex is then “presented” to receptors or T cells that in turn are activated. D–amino acid which are resistant to enzymatic degradation, are not immunogenic. Carbohydrates are not processed or presented and are thus unable to activate T cells, although they can activate B cells.

Requirements for immunogenicity

1. Genetic make up or Genotype

Genetic control of immune responsiveness is largely controlled by gene mapping within the MHC.

2. B and T cell repertoires

Acquired immune responses are triggered following the binding of antigenic epitopes to antigen–specific receptors on B and T lymphocytes. If an individual lacks a particular clone of lymphocytes consisting of cells bearing the identical antigen – specific receptor needed to respond to the stimulus, an immune response to that antigen will not take place.

3. Dosage and route of administration

Insufficient doses of antigen may not stimulate an immune response either because the amount administered fails to activate enough lymphocytes or because such a dose renders the responding cells unresponsive.

4. Number of doses administered

Repeated administration of antigen is required to stimulate a strong immune response.

5. Route of administration

Intravenously administered antigens are carried first to the spleen, whereas those administered using the subcutaneous route travel to the local or draining lymph node. Since immune responses depend upon multiple cellular interactions, the type and extent of the immune response is affected by the cells populating the organ in which the antigen is ultimately delivered.

Types of response to immunogens

1. Primary response

Cells process antigen, triggering antigen–specific lymphocytes to proliferate and differentiate. T–lymphocyte subsets interact with other subsets and induce the latter to differentiate into T–lymphocytes with specialized function. T–lymphocytes also interact with B lymphocytes, inducing them to synthesize and secrete antibodies.

2. Secondary response

a. This second exposure may occur after the response to the first immune event has leveled off or has totally subsided (within weeks or even years). The response has a much quicker onset and much higher magnitude.

b. This secondary (and subsequent) exposure behaves as if the body “remembers” that it had been previously exposed to that same immunogen. In fact, secondary and subsequent responses exploit the expanded number of antigen – specific lymphocytes generated in response to the primary immune response. Thus the increased arsenal of responding lymphocytes accounts, in part, for the magnitude of the response observed.

c. The secondary response is also called the memory or anamnestic response and the B and T lymphocytes that participate in the memory response are termed memory cells.

Major classes of antigens

1. Carbohydrates (polysaccharides)

Polysaccharides are potentially, but not always immunogenic. An excellent example of antigenicity of polysaccharide is the immune response associated with the ABO Blood groups, which are polysaccharides on the surface of red blood cells.

2. Lipids

Lipids are rarely immunogenic and may only be induced if conjugated to a protein carrier thus they can be regarded as haptens.

3. Nucleic acids

Like lipids, nucleic acids only become immunogenic when they are conjugated to protein carriers. An example is the anti – DNA antibodies in systemic lupus erythematosus.

4. Proteins

Virtually all proteins are immunogenic. The greater the degree of complexity of the protein, the more vigorous will be the immune response to that protein.

Cross reaction

Cross reaction is an immunologic reaction in which the immune components, either cells or antibodies react with two molecules that share epitopes, but are otherwise dissimilar.

a. Homologous cross reaction

When two compounds cross react immunologically, the compounds will have one or more epitope in common and the immune response to one of the compounds will recognize one or more of the same epitopes on the other compounds and react with it.

b. Heterologous cross reaction

When antibodies or cells with specificity to one epitope bind, usually more weakly, to another epitope that is not quite identical but has a structural resemblance, to the first epitope.

c. Immunologic cross reaction

A situation in which two or more substances, which may have various degrees of dissimilarity, share epitopes and would therefore react with the immune components induced against anyone of these substances.

Adjuvants

An adjuvant is a substance that, when mixed with an immunogen, enhances the immune response against the immunogen. It is important to distinguish between a carrier for hapten and an adjuvant. A hapten will become immunogenic when conjugated covalently to a carrier; it will not become immunogenic if mixed with an adjuvant. Thus an adjuvant enhances the immune response to immunogens but does not confer immunogenicity on haptens. Alum increases the immunogenicity of immunogens by causing the antigens to precipitate. When injected, the precipitated antigen is released more slowly than antigen alone at the injection site. Moreover, the increased “size” of the antigen, which occurs as a consequence of precipitation, increases the probability that the macromolecule will be phagocytized.

Partial List of CD Antigens

CD Antigen	Other Names	Cellular expression	Function	Ligand
CD1		Langerhans cells, dendritic cells, B cells, thymocytes	MHC class I–like molecule, associated with β2– microglobulin	Glycolipid
CD2	LFA–2	T cells, NK cells	T–cell adhesion molecule	CD58
CD3	T3	T cells	TCR signal transduction
CD4	T4	Thymocytes, TH1 and TH2 T–cells, monocytes, macrophages	TCR coreceptor, signal transduction	MHC class II, HIV –1 and HIV–2
CD5	Tp67 T1	B–cell subsets, T cells	Expression on B cells associated with polyreactivity
CD8		T–cell subsets, cytotoxic T cells	TCR coreceptor, signal transduction	MHC class I
CD11a	LFA–1	Leukocytes	Adhesion molecule	ICAM 1,2,3
CD18		Leukocytes	Associates with CD11a,b,c and d
CD19		B cells	B–cell signal transduction
CD20		B cells	Ca2+ channel in B–cell activation
CD21	CR2	B cells, follicular dendritic cells	Involved in B–cell activation	EBV and complement (C3d)
CD25	TAC	Activated T cells, B cells	IL–2 receptor (α–chain)	IL–2
CD28	Tp44	T–cell subsets	T–cell costimulator molecule	B7 (CD80 and CD86)
CD32	FcϒR II	Monocytes, granulocytes, B cells, eosinophils	Low–affinity receptor for IgG	Aggregated IgG and antigen– antibody complexes
CD34		Endothelial cells, hematopoietic precursors	Marker for early stem cells	L–selectin
CD40		B cells, macrophages, dendritic cells	Involved in T cell interactions with APCs and class switching; receptor for costimulatory signals	CD40L (CD154)
CD44	Pgp–1, H–CAM	Leukocytes, erythrocytes	Lymphocyte adhesion to HEV	Hyaluronic acid
CD50	ICAM–3	Broad (not on endothelial cells)	Adhesion molecule	LFA–1
CD54	ICAM–1	Broad	Adhesion molecule	CD11a, CD18, rhinovirus
CD55	DAF	Broad	Causes dissociation of amplification convertases of complement cascade
CD58	LFA–3	Leukocytes, endothelial cells, epithelial cells, fibroblasts	Adhesion molecule	CD2
CD62L	L–selectin, MEL–14	B cells, T cells, monocytes, NK cells	T–cell adhesion to HEV	CD34
CD74	Invariant chain	B cells, macrophages, monocytes, activated T cells	Associated with MHC class II in endoplasmic reticulum
CD79a	Igα	B cells	Signal transduction molecules, components of B cell receptor
CD79b	Igβ
CD80	B7.1	B cells, macrophages, dendritic cells	Costimulatory molecule on APC	CD28, CTLA–4
CD81	TAPA –1	Broad	Associates with CD19 and CD21 on B cells to form B– cell co–receptor	CD28, CTLA–4
CD86	B7.2	Activated B cells, macrophages, dendritic cells	Costimulatory molecule on APC	CD28, CTLA–4
CD95	Fas, Apo–1	Activated T and B cells, NK cells	Induces apoptosis following ligation with Fas ligand (CD95L)	TNF–like Fas ligand (CD95L)
CD97	GR1	Granulocytes, macrophages, activated T and B cells	Counterreceptor for C55	CD55
CD102	ICAM–2	Endothelial cells, resting lymphocytes, platelets	Adhesion molecule	CD11a (LFA–1)
CD152	CTLA–4	Activated T cells	Negative regulator for T–cell activation	B 7.1 (CD80) and B 7.2 (CD86)
CD154	CD40L	Activated T cells	Ligation with CD40 on B cell proliferation and class switching	CD40

TAPA – target of anti–proliferative antibody

DAF – Decay Accelerating Factor