2. Immune deficiencies 2 Flashcards
What happens in an immune response to a protein antigen?
Initial exposure to Ag induces secretion of IgM followed by IgG. This is a change in isotype or class of immunoglobulin.
CSR: M-G-A-E
Re-exposure induces rapid, robust response with prolonged, high affinity IgG.
The secondary or memory response is of faster kinetics, higher affinity and greater magnitude than the primary response.
*the higher the affinity, the less Ig you need to generate protective response
What response was induced in mice with CD40L-deficiency to immunisation and infection?
Could make IgM to foreign antigen but not IgG1 to immunisation. In response to infection, mice failed to make IgG or memory.
How do Ig isotypes become memory B cells?
When naive B cells become memory cells they change expression of surface markers.
Change of Ig isotype (lose IgD) and gain CD27
Move from bottom right to top left of “dot plots” measuring fluorescence of single cells.
**HIGM patients experience absence of memory B cells in peripheral blood
What are the clinical presentations of HIGM syndromes?
- Clinical symptoms develop during 1st/2nd year of life.
- Common: increased susceptibility to infection inc. upper and lower RT infections by bacteria.
- Lung infections may also occur, caused by viruses (Cytomegalovirus) and fungi (Cryptococcus).
- GI complaints, most commonly diarrhoea and malabsorption
- Enlarged tonsils, spleen, liver, lymph nodes
- Autoimmune disorders may also occur in patients with HIM syndrome, manifestations may inc: chronic arthritis, low platelet counts (thrombocytopenia), haemolytic anemia, hypothyroidism, kidney disease.
What occurs during B cell differentiation to Ab secreting plasma cells?
- Involves substantial remodelling of intracellular organelles
- Requires a highly modifed gene expression program and is tightly regulated
- Dysregulation differentiation causes disease - autoimmunity or immune deficiency, therefore mostly undertaken under strict ‘guidance’ from CD4 T cells
Where is white pulp and red pulp found?
The spleen contains lymphocyte rich regions called white pulp. These form along the blood vessels within the erythrocyte rich regions called red pulp.
*LN contain few erythrocytes and no red pulp.
What is the distribution of lymphocytes within the white pulp in spleen?
B cells and T cells are separated from each other.
What are the early stages of B and T cell activation?
- Antigen enters lymphoid organ, intact into B areas, processed to T
- Ag specific B & T cells are activated by Ag directly or after presentation by DC, which alters chemokine receptor expression:
* T cells express CXCR5
* B cells express CCR7
- once T cells are activated, they change migration pattern slightly, spending more time at boundary to increase chances of initiation with Ag specific B cell in LN
3. Activated B and T cells migrate towards each others areas, meeting at the boundary of T and B cell areas
What two outcomes occur after B cell T cell encounter?
Formation of plasma cells and GC.
-req. correct interaction b/w B and T cells
PLASMA CELLS
- differentiation into short lived plasma cells of low affinity
- first Ab produced
- req. transcription factor Blimp1 in B cells
- increase in ER, Golgi, dedicated to protein synthesis adn secretion
GERMINAL CENTRE FORMATION
- continued B cell proliferation in follicles forms a recognisable GC
- T cell dependent
- req. transcription factor Bcl6
What is Blimp1?
Transcription repressor that shuts off the B cell expression program and permits the plasma cell program
What is Bcl6?
Transcription repressor that promotes cell cycling and inhibits the response to DNA damage (SHM, CSR)
What is a germinal centre (GC)?
Sites within secondary lymphoid organs where mature B lymphocytes prolif, differentiate & mutate their Abs during normal immune response to infection.
Composed of:
- B cells 90%
- CD4+ helper T cells 5%
- Follicular DCs 1%
Define clonal expansion
Activity within GC: T cell driven proliferation of Ag-specific B cells
Define isotype switching
Activity within GC: changing the constant region of the Ab H chain without changing the V region. Specificity is unchanged, however effector function is changed.
Define somatic hypermutation (SHM)
Activity within GC: Random introduction of point mutations into the V gene segments of the H & L chains to diversify binding to Ag.
*Amino acid replacements that improve affinity for Ag are selected for
