Adaptive response; where and when?

Question 1

What are the primary lymphoid organs?

Answer 1

The bone marrow and thymus

Question 2

What are the secondary lymphoid organs?

Answer 2

Lymph nodes, MALT (mucosa-associated lymphoid tissues) and spleen.

Question 3

What are immune cells derived from?

Answer 3

All cells, except for FDCs are derived from hematopoietic stem cells in the bone marrow.

Question 4

Blood infections primarily activate which secondary lymphoid organ?

Answer 4

The spleen

Question 5

Tissue infections primarily activate which secondary lymphoid organs?

Answer 5

Lymph nodes.

Question 6

Mucosal surface infections primarily activate which secondary lymphoid organs?

Answer 6

The mucosal associated lymphoid tissues which line respiratory, gastrointestinal and genitourinary tracts.

Question 7

What process generates the specialised cells of the immune system?

Answer 7

Haematopoisesis

Question 8

Desribe Haemotpoietic stem cells.

Answer 8

They are self-renewing in the bone marrow and are multipotent. There are two pathways; the myeloid and lymphoid. Multipotency is lost when develop into common myeloid/lymphoid progenitor cells.

Question 9

Which cells arise from the myeloid pathway?

Answer 9

erythrocytes, thromobytes, myeloid dendritic cells, monocytes, neutrophils, eosinophils, basophils, mast cells.

Question 10

Which cells arise from the lymphoid pathway?

Answer 10

B and T precursor cells, NK cells, lymphoid dendritic cells. T cell precursors must enter thymus for further specialisation into t cells through recombination of their TCR genes.

Question 11

What occurs once lymphocytes are produced?

Answer 11

Recirculation via blood circulation and lymphatic system.

Question 12

What is the Thoracic duct?

Answer 12

The main connection between the blood and lymphatic systems.

Question 13

How do lymphocytes enter lymph nodes and MALT?

Answer 13

They enter these structures from the circulation, leaving the blood vessels via specialised ares of vascular endothelium termed the high endothelial venules (HEV) directly into the lymph node. They can enter inflammed tissued via diapedesis. Lymph nodes have afferent and efferent systems

Question 14

What does recirculation enable?

Answer 14

Lymphocyte recirculation allows antigen reactive cells to home to the places where they are required with a targeted migration of lymphocytes into the sites where infection may be present. This traffic is mediated through homing molecules on the lymphocyte surface with recognises vascular addressins on the blood vessel endothelium.

Question 15

Describe the structure of the lymph node.

Answer 15

Has an outside collagenous capsule and is connected to the blood circulation. Cortex = outer area and medulla = inner area. Between the cortex and medulla is the paracortex. Main cells in lymph nodes are lymphocytes which are organised into lymphoid follicles.

Question 16

What is the relationship between dendritic cells and lymph nodes?

Answer 16

Dendritic cells recognise PAMPs/DAMPs via PRRs and migrate carrying antigen to the lymph nodes via afferent lymphatics. IDCis now in the lymph node where its long processes interact with T lymphocytes, which has costimulatory molecules (B7). IDCs present antigen to T cell in the paracortex.

Question 17

What do FDCs do?

Answer 17

Present antigens and immune complexes to B cells in the germinal centres of lymph nodes.

Question 18

What are germinal centres?

Answer 18

These are organised strucutres in the secondary lymphoid tissues where all the cells required to initiate an adaptive immune response, such as dendritic cells, helper T cells and B cells, can interact optimally with each other. These are the sites of T and B memory cell generation, antibody class switching, somatic hypermutation (affinity maturation) of B cells and the generation of the precursors of antibody-secreting plasma cells.

Question 19

Describe the anatomy of germinal centres.

Answer 19

Mantle zone, centroblast dark zone, centrocyte in basal light zone, centrocyte in apical light zone. Naive B cell net migration is unidirectional through mantle zone to centrocyte apical light zone

Question 20

Describe the structure of the spleen

Answer 20

There is red and white pulp, with RBS and leukocytes respectively. The periarteriolar lymphoid sheath is a T cell area of white pulp. Within lymphoid sheath if there is an antigen, maturation processes common to lymph nodes.

Question 21

Describe MALT immunity.

Answer 21

Where most infections enter the body, mucous secretions prevent adhesion of pathogens so colonisation cannot occur. Dimeric secretory IgA is transported into the gut by poly-Ig receptors at mucosal surfaces. Dimeric secretory IgA are held together by J chains; a polypeptide. The poly-g (Ig receptor recognises polymerised Igs, also recognises pentameric IgM as it also has a J chain.) Poly-Ig receptor binds to dimeric IgA at basal surface and the complex is then endocytosed by the glandular epithelial cell where it is transported in a vesicle to the apical mucosal surface and is exocytosed. Poly-Ig receptor is then cleaved at apical surface. secretory piece of poly-Ig receptor protects the dimeric IgA and prevents adhesion. IgA is the most important for MALT immunity.

Question 22

What is the most common antibody in the cirulation?

Answer 22

IgG

Question 23

What is the second most common class of antibody?

Answer 23

IgA

Question 24

Where is secretory IgA produced?

Answer 24

At mucosal surfaces produced by plasma cells underlying the mucosal surface. Secretory IgA is dimeric IgA.

Question 25

What is the function of IgA

Answer 25

Prevents adhesion to mucosal surfaces

Question 26

Which is the second most important Ig in MALT immunity?

Answer 26

IgE, which is secreted by plasma cells and sensitises mast cells (have an FcR).

Question 27

What does sensitisation of Mast cells do?

Answer 27

Cuases production of vasoactive amines such as histamine, which attracts eosinophils and neutrophils.

Question 28

How are gut immune responses induced?

Answer 28

Induced in the lymphoid nodules called Peyer’s patches, basal to the intestinal lumen. Microfold cells (M cells) which are modified epithelial cells pick up antigens from lumen of intestine and pass to underlying peyers patches. M cells are located in the crypts of lieberkuhn. Peyers patches then form into germinal centres once activated.

Question 29

How is lymphocyte homing to intestines mediated?

Answer 29

By Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) on vascular endothelium (lamina propria and peyer’s patches). in the gut and is recognised by lymphocyte alpha4beta7 integrin adhesion molecule. This is an example of cell-cell contact dependent adhesion.

Question 30

Name examples of cell-cell contact dependent adhesion

Answer 30

CD80 and CD86 on APCs binding to CD28 on T cells. CD40 binding to CD40L.

Question 31

What are cytokines?

Answer 31

Small 8-80kDA secreted proteins that act as messenger between cells. They can control haematopoiesis and immune responses.

Question 32

What does cytokine-cytokine receptor binding initiate?

Answer 32

intracellular signalling which leads to an increase or decrease expression of genes encoding other cytokines, cell surface and secreted molecules and controls cellular activities such as survival and reproduction.

Question 33

How do cytokines act?

Answer 33

Can act in an endocrine fashion however they more commonly act in either a paracrine or autocrine way.

Question 34

What are the main groups of cytokines?

Answer 34

Interleukins, colony-stimulating factors, chemokines, interferons, TNFs and growth factors.

Question 35

What do interleukins do?

Answer 35

The signal between leukocytes; IL-1 acts as a pyrogen (inflammation)

Question 36

Name three colony stimulating factors

Answer 36

GM-CSF, M-CSF, M-CSF.

Question 37

What are chemokines and what are the four families?

Answer 37

Chemotactic cytokines; C (lymphotactin) CC (RANTES), CXC (IL-8) and CX3C (Fractalkine). Classification is based on cysteine structure. It regulates cell adhesion and leukocyte activation.

Question 38

What do interferons do and what are the different types?

Answer 38

Have antiviral function. Type1 - IFN alpha and beta produced by most nucleating cells of the body. Type2 = IFN-gamma produced by NK and T cell. Regulates the production of Th1 cells and in macropahge activation. All block viral replication.

Question 39

What do TNFs do?

Answer 39

(Alpha and beta) TNF beta = lymphotoxin: macrophage activation, induces endothelial cell adhesion molecules and stimulates cytokine production. IL-1 and IL-6. Involved in inflammation and promotes the acute phase response.

Question 40

What do growth factors do?

Answer 40

Transforming growth factors, TGF beta, mainly inhibitory, inhibits macrophage and dendritic cell activation, inhibits growth of B and T cells, limits inflammation.

Question 41

What are colony stimulating factors?

Answer 41

Granulocyte-macrophage stimulating factor, acts in early myeloid development. M-CSF = monocyte/macrophage colony stimulating factor, induces monocyte differentiation. G-CSF = Granulocyte colony stimulating factor, induces granulocyte differentiation.

Question 42

How do cytokines act?

Answer 42

In a network: pleiotropy= multiple functions on multiple cell types, TNF alpha activates macrophages, induces adhesion molecules on endothelial cells.
Redundancy; IL-2 and IL-15 share many functions- T and B cell proliferation. Synergy; TNFalpha and IFN gamma. Antagonism

Question 43

Can cytokines be used therapeutically?

Answer 43

Yes, IFN for viral infections, however there are pathological aspects of cytokines, autoimmune disorders; blocking antibodies such as anti-TNF alpha for RA. Genetically engineer soluble cytokine receptors such as recombinatn soluble TNF receptor in rheumatoid arthritis.