1. A rough guide to the immune system Dr Adrian Palfreeman Senior Clinical Scientist MRC CTU

2. Stem cells Stem cells –why they matter

3. Neutrophil (polymorph) Multi-lobed nucleus. Commonest leucocyte (2500-7500/mm3 of blood). A short-lived phagocytic cell whose granules contain numerous bactericidal substances. leave the blood to go to tissues where infection or inflammation is developing

4. Eosinophil A leucocyte whose large refractile granules contain a number of highly basic or ‘cationic’ proteins, possibly important in killing larger parasites including worms. Bind avidly to IgE-coated particles (i.e. Helminthic parasites). Abundant at sites of allergic reactions.

5. Components of the immune system

6. Monocyte – The largest nucleated cell of the blood (16-20μm – diameter), developing into a macrophage when it – migrates into the tissues. Macrophage (A professional antigen presenting cell) – The principal resident phagocyte of the tissues. – Strongly phagocytic of particles and microbes. – Has receptors for Ig and complement. – CNS – “microglia” – Liver – “Kupffer cells” – Lungs – “alveolar macrophages” – Bone – “osteoclasts”

8. T lymphocyte (T cell) A thymus-derived (or processed) lymphocyte. 1500 - 4000/mm3 blood 6-15μm diameter (red blood cell 7.2μm diam.) 2 main subdivisions – CD8 (cytotoxic T cells) - CD4 (helper T cells)

11. B lymphocyte – A bone marrow- (or in birds, bursa-) derived lymphocyte, the precursor of antibody-forming cells. In foetal life, the liver may play the role of ‘bursa’. NK (Natural Killer) cells – do not have to recognise a specific antigen before acting against it – are effective against a wide range of infectious microbes.

12. The 2 arms of the adaptive immune response 1. Humoral immunity (antibodies) 2. Cellular immunity (T-cells) Sub-divided into T helper cells (CD4+) and Cytotoxic T cells (CD8+)

13. CD4 Lymphocytes (T helper cells) coordinate much of the immune response to micro-organisms help B-cells respond to foreign proteins secrete substances that enable CD8 T-cells to proliferate activate macrophages so that they can kill certain organisms, including some organisms associated HIV infection.

14. CD8 Lymphocytes (Cytotoxic T cells) kill cells in the body identified as abnormal or foreign tumour cells cells that have been infected by viruses.

15. How does HIV reduce CD4 Cells? Increased turnover of cells in response to infection Trapping of HIV in lymph nodes Shortened survival of CD4 cells Reduced production of new cells Reduction of T cell progenitor production from bone marrow

16. Sites of the principal lymphoid tissues within the human body. Primary lymphoid organs Secondary lymphoid organs

17. Human lymphoid organs Primary lymphoid organs Secondary lymphoid organs

18. Lymphoid tissues – Immune system compartmentalised into organs/tissues. – Funtionally unified via blood and lymph systems. – Lymphocytes recirculate. – In total, equivalent in weight to brain or liver. Primary lymphoid organs – Bone marrow where T and B lymphocytes are made. – Thymus where T lymphocytes mature/are selected. Secondary lymphoid organs – e.g. spleen, lymph nodes and Peyer’s patches. – Contain T cells, B cells, antigen presenting cells (APCs)

19. T cell precursors (thymocytes) migrate from the bone marrow to the thymus to mature. Mature T cells leave the thymus and migrate to secondary lymphoid tissues where they may encounter foreign antigen.

20. Thymus Lobules show - a lymphocyte-dense outer cortex - an inner lighter-staining medulla. Stromal framework with specialised epithelial cells, DCs and macrophages (APCs). T cell precursors arrive from the bone marrow. Cortex and medulla ‘educate’ thymocytes into mature, competent T cells (1 to 3% of T cells survive education). Mature T cells are released into the peripheral circulation.

21. THYMUS Developing thymocytes occupy the interstices of an extensive network of epithelial cells

22. Clusters of Differentiation (CD) CD3 T cells CD4 Helper T cells CD8 Cytotoxic T cells CD16 Macrophages CD19 B cells

23. Maturation of T lymphocytes in the thymus

24. Circulating lymphocytes meet lymph-borne pathogens in draining lymph nodes.

25. Lymph node

27. Cytokines Il2 stimulates division of B and T cells and killing of HIV infected cells by NK cells IL2 levels reduced in HIV infection

28. IL2 Does administration of IL2 help? Raises CD4 numbers Significant side effects Injectable Short term benefit in clinical trials Does it reduce mortality and morbidity in the long term?

29. Summary B cells recognise antigens (antigenic epitopes) via their monomeric IgM receptor T cells recognise antigens (small peptides)via the T cell receptor (TCR) which is always associated at the cell surface with CD3 11 The monomeric B cell receptor (and, in fact, all antibodies) recognise antigens in solution – in their native (folded) state The TCR does not recognise soluble antigens but only small antigenic peptides associated with the Major Histocompatibility (MHC) molecules I & II For a T cell or B cell to be activated 2 appropriate signals are always required T cells need binding of the TCR to peptide/MHC plus specific cytokines from the APC (notably IL- 1 and IL-2) and interaction between B7 and CD28 B cells need binding of mIgM surface receptor plus signals from TH cells (notably IL-4 and IL- 10) and interaction of CD40/CD40L. This process has evolved to prevent unwanted activation of immune cells which can lead to harmful responses such as allergies and autoimmunity