The Immune Response

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The Immune Response

• Immunity, the state of protection from infectious
  disease, has both non-specific and specific
  components.
• The non-specific component, innate immunity, is a
  set of disease resistance mechanisms encoded in
  the germline that are not specific to a
  particular pathogen.
• In contrast, the specific component, adaptive
  immunity, 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.

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Contrasting Characteristics of Innate vs Acquired
Immunity

• 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

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Cells of the Immune System

• All cellular elements of blood arise from
  pluripotent haematopoietic stem cells in bone
  marrow.
• These cells divide to produce two more
  specialised stem cells, a myeloid progenitor and
  a lymphoid progenitor
• These cells have lost the capacity for
  self-renewal but can differentiate into a variety
  of types in response to a range of growth factors

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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
  cytoplasmnucleus ratio and increased organellar
  complexity.
• Lymphocytes can be subdivided into three
  populations

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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 lymphoid organs.
• These can be divided into the primary or central
  lymphoid organs and the secondary or peripheral
  lymphoid organs.

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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.

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Secondary Lymphoid Organs

• A network of organised lymphoid tissues placed at
  strategic points around the body
• Comprises lymph nodes 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 Peyers 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

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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 the medulla which 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.

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Spleen

• Spleen not supplied 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 marginal zone which
  is rich in B cell follicles.

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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.

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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

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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. Graves
  disease

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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 self Major
  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

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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

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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

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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.

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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

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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

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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.

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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

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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

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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

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Summary - adaptive/acquired immunity

• Specificity
• Diversity
• Memory
• Self/non-self discrimination