12. Lymphoid Tissues Flashcards
Where is the thymus? Describe it.
What cell types does the thymus contain?
Anterior mediastinum above heart. Bilobed, each lobe comprises many lobules, which each have a central medulla and outer cortex.
Thymic epithelial cells, dendritic cells, macrophages, developing T-cells known as thymocytes.
Describe the development of thymocytes from cortex to medulla.
Start in cortex, progress through the following stages: (TCR=t-cell receptor)
- Start as TCR -ve, CD4 -ve, CD8 -ve (double negative thymocytes)
- Then express a bit of TCR (1 chain out of 2): TCRb +ve, TCRa -ve, CD4 -ve, CD8 -ve
- Then express whole TCR (both chains) and CD4 and CD8: TCRab, CD4+ve, CD8+ve (double positive)
Move to medulla, become either:
•Single-positive thymocytes expressing , TCRab +ve, CD4 +ve, CD8 -ve,
•Or Single positive thymocytes expressing TCRab +ve, CD4 -ve, CD8 +ve.
Distinguish between positive and negative selection.
What happens to thymocytes that are not positively or negatively selected?
Positive selection: in cortex on HLA molecules (and peptides) expressed on thymic epithelial cells: only cells whose TCR interacts with self class I and II HLA molecules survive. Whether the TCR interacts better with class I or II HLA determines the commitment to CD4/CD8 lineage.
Negative selection: in cortex and medulla against self peptides on self HLA molecules presented by thymic epithelial cells and dendritic cells. Any thymocyte whose TCR enthusiastically binds a self HLA molecule plus a self peptide is deleted: clonal deletion
Apoptosis. Macrophages clear up debris. Surviving single positive thymocytes pass into blood as mature naive CD4 or CD8 T-lymphocytes.
What types of cells are found in bone marrow?
Describe the structure of a lymph node.
What cells are found in the cortex, paracortex and medulla?
How can lymphocytes leave the blood when the enter a lymph node?
Pluripotent bone marrow stem cells, myeloid linage cells, lymphoid lineage to B-cells, precursor T-cells and Null cells. Many mature plasma cells.
Outer capsule and trabeculae are dense fibrous tissue with collagen, and the whole interior is supported by delicate reticular fibres. The subcapsular sinus is lined by macrophages.
Cortex: B-cells mainly, follicular dendritic cells, tingible body macrophages. Germinal centres occur within some follicles (secondary follicles), and contain fast-dividing B-lymphocytes, with some CD4 T-lymphocytes.
Paracortex: T-lymphocytes and dendritic cells (interdigitating)
Medulla: macrophages, plasma cells.
Via high endothelial venules (HEV)
Describe what happens when an antigen enters the afferent lymphatics (either as free microbes, particles, or within phagocytes and dendritic cells).
How do the rapidly expanding B-cells form subclones?
B-cells initially encounter antigen in cortex outside follicles. Antigen presentation to T-lymphocytes in paracortex. Once activated, Th2 CD4 T-cells enter cortex and meet B-cells. Initial B-cell activation and proliferation, with some differentiation to plasma cells occurs. The B-cells that are most strongly activated move into follicle with CD4 T-cells that are helping them, proliferate, and form a germinal centre. The antigen is trapped and made available for B-cells by folliclar dendritic cells.
Due to somatic mutation of variable region gene - alter specificity. Subclones compete for antigen binding. CD4 T-cells continually monitor antigen presented by B-cells: if somatic mutation causes autoreactivity, help is withdrawn.
Describe the structure of the spleen.
Describe the formation of T-cells, from SC to mature naive.
What happens after the mature naive T-cells enter the blood?
Capsule and trabeculae are dense fibrous tissue, with collagen. Whole interior supported by fine reticular fibres. Red pulp = RBC being examined for defects. Arterioles have periarteriolar lymphoid sheath around (PALS)
Derived from pluripotent stem cells in bone marrow. Precursors colonise thymus. Antigen receptor is TCR (not CD4/CD8). TCR genes are rearranged randomly. Expresses TCR first with both CD4 and CD8, then chooses one. If recognises antigen (correctly presented on HLA molecule) will be deleted. Many autoreactive clones deleted here in thymus. If they survive this: leave thymus as mature naive T-cell expressing TCR and either CD4 or CD8 -> blood
Enters lymph at high endothelial venules in lymph node. Spends time in paracortical region of LN where dendritic cells pletiful.
Describe the path of dendritic cells.
Where does initial presentation of antigen to mature naive T-cells (CD4/CD8) occur? How are dendritic cells involved?
Travel around body, from tissues, skin etc. entering lymph, arriving at LN, spending time in paracortical region, moving from LN to LN, then moving back to blood and tissues.
In paracortical region. If dendritic cell does not “sense danger” (necrotic products, denatured proteins, inflammatory mediators etc.), then it won’t deliver the “second signal” to T-cells (via CD80, IL12 etc.). If a T-cell that recognises antigen does not receive this “second signal it dies or becomes anergic. Second chance for autoreactive T-cells to become anergic or be deleted.
Once activated, CD4 T-cell must choose whether to become one of which two types of cell?
What are:
a) regulatory T-cells?
b) gamma-delta T-cells?
Th1 CD4 T-cells (helping macrophages with gamma interferon), Th2 CD4 T-cells (helping B-cells with IL4) - these cells immediately meet up with B-cells in cortex, otherwise the T-cells migrate around body.
a) Subpopulation of T-cells, modulate immune system, maintain tolerance to self-antigens, prevent autoimmune disease. Immunosuppressive and generally suppress or downregulate induction and proliferation of effector T-cells. Express CD4, CD25 and FoxP3 biomarkers. 3rd line of defence - can turn off autoreactive Tcells not inactivated by dendritic cells
b) T-cells that use different TCR encoded at different genes (gamma and delta chains, encoded at gamma and delta gene complexes). Special populations live in certain places e.g. skin but we don’t know what they’re recognising
Where do B-cells develop from?
Describe what happens when the B-lymphocyte first expresses an antibody, to when it becomes a mature naive B-cell.
Pluripotent bone marrow stem cell, via lymphoid lineage. Antibody is antigen receptor.
Rearranges Ab genes randomly, first expresses Ab in IgM form. V. sensitive to deletion if binds antigen. Many autoreactive clones deleted here (negative selection). Clones for specific pathogens in bone marrow will also be deleted (but are pre-existing clones in periperhy specific for such pathogens). If they survive this -> become mature naive B-cells. Expresses Ab in IgM and IgD form (same variable region on each, in any 1 B-cell).
What does a mature naive B-cell do once it has been formed?
What happens when it encounters an antigen that its antibody fits?
Travels in blood, visits lymph nodes (and spleen and other lymphoid tissue). Leaves blood via high endothelial venules in LNs. Spends time in the cortex of lymph nodes, including in follicles. Travels through lymphatic system, rejoins blood via thoracic duct etc.
Response depends on whether antigen has repeated determinants. If it does, antigen is T-independent (no T-cell help required for initial response e.g. recognises polysaccharide capsule of bacteria). If it doesn’t: T-dependent antigen, must be endocytosed, digested, and presented on class II HLA to CD4 T-cells. If recognised by CD4 T-cell, receives help via CD154→CD40, and via IL4, IL5, IL13, & IL6. When first activated, the B-cell again expresses its antibody in the form of IgM.
What happens if a B-cell does not receive help after engaging with T-dependent antigen?
What happens if the B-cell is activated? Where does the B-cell usually encounter the antigen and T-cell?
What happens after the activated B-cell encounters the T-cell?
Dies or becomes anergic. Second chance for autoreactive B-cells to be deleted.
Forms clone. Individual members of clone may undergo: class switching, further mutation of Ab genes (compete against each other so ones that fit antigen best get t divide up), or differentiation to form plasma cell. Antigen = anywhere. T-cell = usually in lymphoid tissue, in cortex outside follicles. Initial response happens there, plasma cell secreting IgM Abs may be generated there.
A few activated B-cells move into follicle with relevant CD4 T-cells. Rapid replication forming germinal centre, other B-cells pushed aside into mantle zone. Somatic mutation takes place here, creating subclones which compete for antigen to bind to. Subclones which are less adapted to binding that antigen will die. The subclones that bind best will prosper.
Aside from the activated B-cells and T-cells, what other cells are in the follicle/germinal centre in the thymus?
What do CD8 T-cells and NK cells (null lymphocytes) do?
Tingible body macrophages (prominent lysosomes) to phagocytose dead cells/failed B cells. Follicular dendritic cells, trap antigen making it availble for B-cells to bind to. More plasma cells (generated from cells derived from germinal centres) which migrate to medulla, spleen and bone marrow. Also many macrophages in subcapsular sinus and medulla of LN.
Both kill self cells via perforin secretion (makes holes in target cell membrane), and injection of granzymes (generate reactive oxygen radicals and trigger apoptosis in target cell). CD8 also expreses Fas ligand which interacts with Fas on target cell -> initiates apoptosis. If cell does not respond to Fas ligand, CD8 can make holes via perforin and inject granzymes.
What is the ‘killer (K) activity’ of NK cells?
What other receptors do they express?
Give 2 features of NK cells that are like the:
a) innate immune system
b) adaptive immune system
They express an Fc receptor for IgG, so can kill cells to which an Ab is attached.
Killer inhibitory receptors (KIR) which recognise class I HLA molecules on target cell and inhibit killing if they do (thus HLA acting as self marker, thus cells that lack class I are killed by NK cells).
a) multiple different receptors on each cell. No clonal expansion giving memory
b) NK cells differ from each other b/c they have different combination of receptors. Some degree of deletion and down-regulation of clones to acheive self-tolerance.
BUT OVERALL PART OF THE INNATE IMMUNE SYSTEM
Describe the following biomarkers:
a) CD25
b) CD19
c) CD56
a) IL2 receptor, present on activated T-cells and T-reg lymphocytes.
b) on B-cells, aggregate on cell surface with Ab.
c) present on NK cells, and neurones, glia, skeletal muscle. Adhesion molecule.
Which classes of Ab appears first in the immune response?
Which type of hypersensitivity involves immune complexes and innocent bystander damage?
Which cells are involved in auto-immunity and damage?
IgM (expressed by immature B cells in the bone marrow)
(NB: IgG more characteristic of second response, IgA in later responses, IgE to do with mast cells, IdG never secreted - on mature naive B cell)
3
Adaptive immune response - B and T cells
