Immune Responses: Primary and Secondary

Abstract

Immune responses to antigens may be categorised as primary or secondary responses. The primary immune response of the body to antigen occurs on the first occasion it is encountered. Depending on the nature of the antigen and the site of entry this response can take up to 14 days to resolve and leads to the generation of memory cells with a high specificity for the inducing antigen. The humoral response, mediated by B cells with the help of T cells, produces high‐affinity and antigen‐specific antibodies. This is in contrast with the CD8 T‐cell response which leads to the generation of large numbers of antigen‐specific cells that are capable of directly killing infected cells. Antigen‐specific CD4 T cells, which provide help to B cells in the form of cytokines and other stimulatory factors, can also be expanded upon antigenic stimulation.

The secondary response of both B‐ and T cells is observed following subsequent encounter with the same antigen and is more rapid leading to the activation of previously generated memory cells. This has some quantitative and qualitative differences from the primary response.

Key Concepts:

  • The innate immune system is the first line of defence against infectious agents. When this is breached, the adaptive immune system provides a more efficient response to clearing pathogens.

  • The adaptive immune system has the capacity to ‘remember’ previous antigens, a process termed immunological memory.

  • Antigen‐specific T cells are selected during a primary immune response and expand to produce clones of T cells with high specificity for the activating antigen.

  • In a B cell primary response to a thymus‐dependent antigen, the immune system selects B cells with a high affinity and specificity for the antigen and these become memory cells.

  • The selection of B cells with a high affinity for a given antigen occurs in the germinal centres of secondary lymphoid follicles and requires the enzyme activation‐induced cytidine deaminase (AID) and interactions with other immune cells.

  • The ability to change the isotype of antibody produced (class switching) by a B cell also occurs in germinal centres and requires AID.

  • In a secondary response to the same antigen, memory cells are rapidly activated. This process is quicker and more effective than the primary response.

Keywords: antigens; memory cells; clonal expansion; germinal centres; affinity maturation; class switching

Figure 1.

Characteristics of primary and secondary antibody responses. The major antibody class elicited during the primary immune response is immunoglobulin M (IgM) (red line) although low levels of IgG (blue line) may be detected. Antibodies of both classes are of low affinity. The levels of antibody subsequently decline. Following further challenge with the same (but not unrelated antigen) there is a prompt response resulting in the production of IgG antibodies of increasing affinity (dashed line). The affinity of the IgM antibodies remains essentially unchanged. The precise pattern observed is dependent on the nature of the antigen, route of administration, presence or absence of adjuvant and the species and strain of animal. The data are presented on a logarithmic scale.

Figure 2.

Characteristics of primary and secondary cellular responses. The figure presented represents the response of a strain of mice to influenza A virus administered intranasally on two occasions, eight months apart. The development of CD8 T cells specific for the virus was determined using a complex of influenza antigen (peptide), major histocompatibility complex (MHC) class I molecules and the molecule avidin which permits specific cells to be determined in a fluorescence‐activated cell sorter. Note that rechallenging the mice eight months after the initial challenge results in the development of a prompter and greater cytotoxic CD8 T‐cell response in the lungs. Based on data presented by Flynn et al..

Figure 3.

The primary and secondary antibody response and clonal expansion of B cells. In the primary response, initial encounter with antigen X stimulates naïve B cells expressing the relevant receptor to proliferate and differentiate into plasma cells secreting specific antibodies. A small proportion of the antigen‐stimulated B cells survive as memory cells. When antigen X is encountered on a subsequent occasion antibody is produced more rapidly and in greater quantity due to the presence of memory cells. This enhanced response is specific for antigen X thus simultaneous challenge with antigen (Y) to which the host has not previously been exposed will produce a primary response. The same principle can explain memory T‐cell responses. The antibody concentration is plotted on a log scale. Time points have been omitted as the speed of the response depends on a variety of factors. Reprinted from Staines NA, Brostoff J and James K (1993) Introducing Immunology, 2nd edn, p. 26. St Louis: Mosby. Copyright © 1993 by permission of the publisher Mosby.

Figure 4.

The germinal centre response. Germinal centres are formed when cells activated by exposure to antigen in secondary lymphoid tissues migrate, along with T cells involved in their activation, into primary lymphoid follicles. The germinal centre which results contains B cells, follicular dendritic cells (FDCs) and some T cells. These cells are distributed in two distinct zones, the dark and light zones, through which activated B cells transit during their development into plasma cells or memory cells. The reactions that occur are as follows. The activated B cells, called centroblasts (CB), enter the primary lymphoid follicle where they undergo rapid proliferation and somatic hypermutation, forming the dark zone. This results in clones of cells known as centrocytes (CC), the progeny of each clone bearing immunoglobulin receptors of unique affinity for the inducing antigen. Centrocytes migrate into the light zone where they come into contact with a network of FDCs expressing antigen/antibody complexes on their surface. Centrocytes expressing high‐affinity receptors preferentially bind these complexes and are thus selected for survival and further maturation. In contrast, centrocytes expressing low‐affinity receptors fail to bind to FDC and die by apoptosis (dashed arrows). This positive selection process may be repeated on subsequent immunisations, resulting in antibodies of increasing affinity. The centrocytes selected for survival engage in both antigen‐specific and co‐stimulatory molecule‐mediated interactions with T cells. These induce further proliferation and differentiation into either memory B cells or plasma cells (PC).

Figure 5.

Immunoglobulin class switching. A number of genes code for each class of immunoglobulin and these genes are arranged along the chromosome in a defined order. They consist of the genes which code for the variable region (the VDJ genes) of the molecule, which are the same in all antibodies of a given specificity irrespective of class, and those which code for the constant region of the heavy chain of each different immunoglobulin class. In the initial phases of the primary immune response the variable region genes, which determine antibody specificity, are linked to the closest heavy chain gene on the chromosome, normally that coding for the immunoglobulin M (IgM) isotype (A). Later in the immune response (especially after re‐exposure to antigens) the variable region genes may become associated with other heavy chain genes further along the chromosome. This association is achieved by the deletion of the intervening DNA sequences on the chromosome by enzymes known as switch recombinases which cleave the DNA at susceptible sites known as switch regions (coloured circles) (B). In this simple scheme the switch of antibody production from IgM to IgA1, a subclass of IgA, is depicted (B, C and D).

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References

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Further Reading

Jameson SC and Masopust D (2009) Diversity in T cell memory: an embarrassment of riches. Immunity 31: 859–871.

Lanzavecchia A and Sallusto F (2005) Understanding the generation and function of memory T cells. Current Opinion in Immunology 17: 326–332.

Manz RA, Hauser AE, Hiepe F and Radbruch A (2005) Maintenance of serum antibody levels. Annual Reviews Immunology 23: 367–386.

McHeyzer‐Williams LJ and McHeyzer‐Williams MG (2005) Antigen‐specific memory B cell development. Annual Reviews Immunology 23: 487–513.

Murphy KM, Travers P and Walport M (2008) Janeway's Immunobiology, 7th edn. New York: Garland Publishing.

Paul WE (ed.) (1998) Fundamental Immunology. Philadelphia: Lippincott‐Raven.

Tangye SG and Tarlinton DM (2009) Memory B cells: effectors of long‐lived immune responses. European Journal of Immunology 39: 2065–2075.

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Ademokun, Alexander A, and Dunn‐Walters, Deborah(Sep 2010) Immune Responses: Primary and Secondary. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000947.pub2]