Immunology Notes

Immunology

1. Acquired immunity

Primary lymphoid tissues are where lymphocytes are generated and matured. Primary lymphoid tissues include:

• Bone marrow

• Thymus gland

• The bursa of fabricus in birds

• Ileal Peyers patches in sheep, cattle, pigs, dogs and horses

• The caecal patch in rabbits.

Secondary lymphoid tissues are where lymphocytes interact with antigen presenting cells (APCs). These include:

• Lymph nodes

• Mucosal-associated lymphoid tissue (MALT)

• Spleen

Lymphocytes are formed from lymphoid stem cells and blast cells in the bone marrow. These also form natural killer cells.

B lymphocytes are responsible for producing plasma cells, and form the humoral immune response.

T lymphocytes may be of the CD4+ helper or CD8+ cytotoxic type, and form the cellular immune response.

Each type of lymphocyte expresses thousands of identical receptors, unique for a single antigenic peptide.

1. T lymphocytes

Cytotoxic T lymphocytes (CTLs) express CD8 and are MHC (major histocompatibility complex) class I restricted. They kill cells infected with intracellular pathogens. CTLs work through the effectors IFN-gamma, TNF-beta, TNF-alpha, perforin, granzymes and Fas ligand.

Helper T lymphocytes (TH) express CD4 and are MHC class II restricted. Th1 cells are pro-inflammatory. They respond to TNF-alpha, IFN-gamma, and IL12 to activate effectors (such as CTLs) to kill intracellular pathogens. They work through the effectors of IFN-gamma, GM-CSF, TNF-alpha, IL-3, TNF-beta, IL-2 and CD40 ligand.

Th2 cells are anti-inflammatory. They stimulate antibody production by B lymphocytes and class switching. They work through the effectors of IL-4, IL-5, IL-13, IL-10, TGF-beta, GM-CSF and CD40 ligand.

T cell receptors (TCR) remain more constant than B cell receptors (BCR). The receptors of a single T cell are identical and unique to a single epitope, with variation between T cells. Diversity is essential for coverage by the immune system. Each cell has a single type of binding site on its TCR, and there are around 30,000 identical TCRs on each T cell.

T cell receptors have two forms, either alpha/beta (95%) homodimers, or gamma/delta (5%, although more common in cattle) heterodimers.

Alpha/beta homodimers are classical MHC class I or II restricted and membrane bound.

Gamma/delta heterodimers may be restricted by non-classical MHC class I and bind free, specialised antigens such as non-peptides or phosphorylated ligands.

Somatic DNA recombination occurs in developing lymphocytes to satisfy the need for diversity.

T cells must have antigen presented to them in complex of MHC and peptide. MHC is complex glycoprotein. Processes antigenic protein is presented to the T cell as a peptide in the groove of the MHC molecules, which is restricted by the MHC class.

MHC class I is expressed on all nucleated cells in the body except red blood cells, platelets and nerve cells. MHC class II is expressed only on the surface of professional antigen presenting cells (APCs). Both classes show considerable genetic variation between individuals known as MHC heterozygosity. This can contribute to disease resistance. MHC functions to transport samples of intracellular proteins to the cell surface. This is part of normal physiology, and normal peptides produced will be expressed. Circulating T cells do not respond to ‘self’ protein expressed by MHC molecules. If the cell is abnormal, the peptides which are expressed alter. These are recognised by circulating T cells.

Although MHC primarily binds to T or B cell receptors, CD4 and CD8 can bind MHC molecules at sites distal to the peptide cleft. This binding stabilises the APC/lymphocyte interaction, reinforcing MHC restriction.

In the presence of co-stimulation, clonal expansion occurs. Co-stimulatory signals occur to induce the T cell driven adaptive immune response. The primary co-stimulatory signal is antigen specific and is the TCR interaction with peptide-MHC molecules. Secondary co-stimulatory signals are antigen non-specific and is provided by the interaction between co-stimulatory molecules expressed on the membrane of the APC and the T cell, such as CD40 on the APC and CD154 on the T cell. The secondary signals amplify T cell activation.

Upon antigenic and co-stimulation, the cell enlarges, stops migrating and chromatin becomes less dense. Within hours the cell looks different and is referred to as a lymphoblast. Lymphoblasts can divide, giving rise to 2-4 daughter cells every 24 hours. This phase lasts 3-5 days.

2. B cells and antibodies

B lymphocytes have B cell receptors (BCRs) known as immunoglobulins (Ig). IgM is expressed when the B cell is immature and can bind up to 10 antigens simultaneously. IgD is also expressed at the B cell matures. They also express MHC II, which they use to present antigen to T cells.

For optimal function, B cells must have antigen presented to them and be in contact with Th2 cells in T cell areas of lymphoid tissue. Cytokines IL-4 and IL-5 (produced by Th2 cells) stimulate B cell proliferation.

Germinal centres form in lymph nodes where T and B cells interact and B cells proliferate. Some B cells remain in the lymph node whilst others emigrate to the site of antigen. B cells stop mitosis. Some establish memory cells whilst others differentiate into plasma cells. Antibody is synthesised by blasting B lymphocytes and plasma cells.

B cells can give a primary or a secondary response, depending on whether the antigen has been encountered before.

Primary responses are short-lived and low magnitude. The isotype is IgM, and the response is initiated in the local lymph nodes where antigen is presented to naïve lymphocytes. From this response, memory cells are established.

Secondary responses occur when the same antigen is encountered again. They are more rapid due to the recall of memory cells, have a longer duration and a higher magnitude. They are initiated in local lymphoid tissues by the activation of primed lymphocytes. The isotype switches from IgM to...

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