The Immune Response

1. The Immune Response • Immunity, the state of protection from infectious disease, has both non-specific and specificcomponents. • The non-specific component, innateimmunity, is a set of disease resistance mechanisms encoded in the germline that are not specific to a particular pathogen. • In contrast, the specific component, adaptiveimmunity, displays specificity and “memory”. • Some form of innate immunity is present in all multicellular organisms whereas adaptive immunity evolved 400 million years ago and is only found in cartilaginous and bony fish, amphibians, reptiles, birds and mammals.

2. Innate Immunity Characteristics non-specific, present at birth, does not change in intensity with exposure Components Mechanical & physiological barriers, secreted products and cells Acquired Immunity Characteristics Specific responses, acquired from exposure, increases in intensity with exposure Components Secreted products and cells Contrasting Characteristics of Innate vs Acquired Immunity

3. Cells of the Immune System • All cellular elements of blood arise from pluripotenthaematopoietic stem cells in bone marrow. • These cells divide to produce two more specialised stem cells, a myeloidprogenitor and a lymphoidprogenitor • These cells have lost the capacity for self-renewal but can differentiate into a variety of types in response to a range of growthfactors

4. LYMPHOID LINEAGE • Constitute 20-40% of white blood cells and 99% of cells in lymph. • Approximately 1011 lymphocytes in the human body and are central components of the adaptive immune response. • Resting lymphocytes generally small, motile, nonphagocytic cells which cannot be distinguished morphologically. • Cytoplasm forms a narrow rim around nucleus and have densely packed chromatin, few mitochondria and poorly developed endoplasmic reticulum and Golgi apparatus. • When activated (by interaction with antigen) enlarge into lymphoblasts which have higher cytoplasm:nucleus ratio and increased organellar complexity. • Lymphocytes can be subdivided into three populations

5. Lymphoid Organs • All of the cells of the immune system are initially derived from the bone marrow. • These cells, particularly the lymphocytes, mature in, and recirculate around, the lymphoidorgans. • These can be divided into the primary or central lymphoid organs and the secondary or peripheral lymphoid organs.

6. Primary Lymphoid Organs • The primary lymphoid organs are the bone marrow and the thymus, a large organ overlying the heart. • B lymphocytes are produced in the bone marrow and mature there. • T lymphocytes leave the bone marrow and mature in the thymus.

7. Secondary Lymphoid Organs • A network of organised lymphoid tissues placed at strategic points around the body • Comprises lymphnodes and white pulp areas of the spleen • Can also be subdivided into anatomical compartments e.g. gut-associated lymphoid tissues (GALT) includes the tonsils, adenoids, appendix and Peyer’s patches. • Structures are connected by the lymphatic vessels which drain the extracellular fluid (lymph) from tissues. • System designed to constantly sample material (antigen) from all of the tissues of the body and transport it to secondary lymphoid tissues to meet constantly recirculating lymphocytes • System provides constant immune surveillance

8. Lymph Nodes • Morphologically lymph node vaguely comprises three concentric rings. • Outer thymus-independent cortex comprises B cells, macrophages and follicular dendritic cells organised into primary follicles. • Beneath this is thymus-dependent area or paracortex which contains mainly T cells and interdigitating dendritic cells (IDC). • At the centre is themedullawhich is primarily populated by antibody secreting plasma cells. • After antigen enters a lymph node in afferent lymph it percolates through these areas to be trapped by the network of phagocytic cells and dendritic cells (FDC and IDC). Antigen trapped on IDC is presented to T cells which become activated and then move to follicles to help B cells become fully activated.

9. Spleen • Spleen notsupplied by lymphatic vessels • Blood-borne antigens enter via the splenic artery. • Lymph nodes are main mechanism of surveillance for tissue, spleen filters blood to trap blood-borne antigen. • Spleen comprises two compartments. • Red pulp primarily concerned with removal of effete erythrocytes. • White pulp surrounds the branches of the splenic artery to form the peri-arteriolar lymphoid sheath (PALS), which contains mainly T cells. Associated with this is the marginalzone which is rich in B cell follicles.

10. B cells • Derived their letter of designation as a result of early studies demonstrating their maturation in the bursa of Fabricius in birds • Name apt as bone marrow is major site of production and maturation of B cells. • Mature B cells definitively distinguished from other lymphocytes by synthesis and display of membrane-bound immunoglobulin. • After recognition of antigen B cells differentiate into plasma cells which produce antibody.

11. B cells • ‘See’ foreign protein (antigen) via their surface immunoglobulin • ‘See’ parts of native antigen and tertiary (3D) structure of this • Produce antibody which is secreted form of their surface immunoglobulin • Often ‘helped’ by T cells • Display ‘memory’

12. B cells • Deficiencies in B cell responses can result in susceptibility to infection e.g. X-linked hypergammaglobulinaemia • Inappropriate/misdirected/excessive B cell responses may result in autoimmunity e.g. Grave’s disease

13. T cells • Derive name from site of maturation in Thymus. • Each T cell expresses a single specificity of T cell receptor complex on surface. • Each T cell receptor ‘sees’ a particular portion of antigen (peptide) in context of selfMajor Histocompatibility Complex (MHC) on antigen presenting cells (APC) • T cells from a particular individual only ‘see’ particular peptides presented in the context of MHC molecules expressed by that individual - MHC restriction • T cell has specificity for combination of peptide + MHC

14. T cells • CD8+ T cells ‘see’ peptide in context of MHC I • CD4+ T cells ‘see’ peptide in context of MHC II • Deficiencies in T cell responses can result in susceptibility to infection • Inappropriate/misdirected/excessive T cell responses may result in autoimmunity • Display ‘memory’

15. MHC - Major Histocompatibility Complex • Human Leukocyte Antigen (HLA) genes in humans • H-2 genes in mice • Class I, presentation to CD8+ T cells, encoded by • HLA-A, -B, -C in humans • H2 -K, -D, -L in mice • Class II, presentation to CD4+ T cells, encoded by • HLA-DR, -DP, DQ in humans • H-2A, -E in mice

16. MHC - Major Histocompatibility Complex • MHC is polygenic • There are several different class I and class II genes • MHC is polymorphic • There are multiple variants (alleles) of each gene within the population • The combination of polygeny and polymorphism mean that there is a wide diversity of MHC genes at both the individual and population level.

17. Antigen Presenting Cells - APC • Specialised phagocytic cells which acquire proteins and process them for presentation to T cells in the context of MHC • e.g. dendritic cells, macrophages, B cells

18. CD8+ T cells • CD8+ T cells ‘see’ peptide presented on APC in context of MHC I. • CD8+ T cells are generally T cytotoxic (Tc) T cells. • CD8+ T cells are generally important for killing cells containing intracellular pathogens (particularly viruses) and controlling tumours. • Deficiencies in CD8+ T cell responses can result in susceptibility to infection • Inappropriate/misdirected/excessive CD8+ T cell responses may result in autoimmunity

19. CD4+ T cells • CD4+ T cells generally function as T helper (TH) cells. • Help or control other cells by expression of surface molecules (cognate interaction) or secretion of soluble mediators (cytokines). • CD4+ T cells can be further subdivided into two subsets. • TH1 cells ‘help’ cell mediated immune responses. • TH2 cells ‘help’ B cell responses.

20. TH1 cells • TH1 cells ‘help’ cell mediated immune (CMI) responses, often by production of cytokines such as IFNg. • Important for activating phagocytic cells to kill intracellular pathogens they have consumed e.g. protozoa such as Leishmania, mycobacteria etc • Deficiencies in TH1 cell responses can result in susceptibility to infection e.g. mycobacteria • Inappropriate/misdirected/excessive TH1 responses may result in autoimmune/inflammatory disease e.g. rheumatoid arthritis, IBD etc

21. TH2 cells • TH2 cells ‘help’ cell humoral immune responses, often by production of cytokines such as Interleukin 4 (IL-4). • Important for protection against extracellular pathogens e.g. metazoa such as helminths etc • Deficiencies in TH2 cell responses can result in susceptibility to infection e.g. helminths • Inappropriate/misdirected/excessive TH2 responses may result in autoimmune/inflammatory disease e.g. asthma

22. Memory and self/non-self • Cells of the adaptive immune response are altered by initial encounter with antigen and persist • Subsequent responses are faster, bigger and better - anamnestic • Responses are usually directed against ‘foreign’ antigens (non-self) and not against self antigens

23. Summary - adaptive/acquired immunity • Specificity • Diversity • Memory • Self/non-self discrimination