Sites and structure of primary lymphoid organs

(B cells and T cells)

• Bone marrow is the site of the production of immature B and T cells from the common lymphoid progenitor
• B cells are released as immature B cells, then released into the blood to mature in secondary lymphoid organs
• T cells - enter thymus as the haematopoietic precusor, migration into inner and outer cortex as a DN1/2/3/4 cell, before interaction with cortical epithelial cells cause expression of both receptor types, therefore inducing DP thymcytes. Further interaction activates either MHC-1 (CD8) or MHC-II (CD4) recognition to commit cell to cell line - positive and negative selection with medullary epithelial cells or dendritic cells within the medulla produce SP T cells. 

Secondary lymphoid organs

(structure and function)

• Spleen - seperated into capsule, trabecula, red pulp, primary follicles and germinal centres
• Function - to monitor blood for pathogens and activate lymphocytes accordingly
• Red pulp - mechanical filtration of red blood cells, acting as reserve for monocytes
• White pulp - lymphoid follicles containing immature B cells for activation, periarteriolar lymphoid sheaths containing developed T lymphocytes for selection
• Lymph nodes contain germinal centres within the cortex, which contain the B cells for activation and selection. Paracortex contains T cells for selection, while both cell types, once activated exit through the efferent lymphatic vessels
• Lymph nodes act to monitor the extracellular matrix of solid tissues for pathogens/PAMPs

• Antigenicity is the capacity of a chemical structure (e.g. antigen) to bind to receptors which mediate adaptive immunity (B cell/T cell receptors)
• Immunogeneicity is the ability to to induce a humoral and cell mediated response 
• Thymus independent antigens (weak antigens) produce humoral response (IgM) without T cell involvement, while TD antigens require Th involvement and therefore class switching to IgG isotype/ memory cell formation (strong antigens)
• TI antigens are generally repetitive and are TLR ligands while TD antigens are protein epitopes

MHC-I vs MHC-II signalling

(cell types and antigen types)

• MHC-I - short peptide fragments from intracellular pathogens, expressed on all nucleated cells 
• MHC-II - longer peptide fragments from extracellular pathogens, expressed on APCs only
• MHC-I proteins are processed through normal proteasome catalysis - ubiquitination and destruction by proteasome. Protein fragments transported into ER through TAP, attached to chaperones and thus MHC-I, then transported out of ER and onto cell surface via Golgi
• MHC-II - endocytosis of antigen by APCs (or virus particle) destoyed in endolysosome - MHC-II present in vesicle - present to CD4 cells on cell surface
• Professional APCs can cross present internalised proteins on MHC-I recruited from ER into endosome.

Immunoglobulin structure 

(chains and variation mechanisms)

• 2 heavy chains - made from 2 conserved regions (Fc - effector function) and 1 conserved, 1 variable region joined by hinge
• 2 Light chain - made from 1 conserved and one variable region attached by sulphide bridges
• Variable regions of heavy and light chains make Fab portion - specificity (CDR - complementary determining region)
• Diversity - gene rearrangment of variable and diversity regions, somatic gene rearrangment, D region transcribed in multiple domains, inprecise joining, random insertion and deletion of nucleotides in regions flanking joining sites, random pairing of D and L chains. 
• After selection of B-cell - activation of activation induced deaminase (AID) to convert cytosine to uracil in hypervariable hotspots, while error prone DNA repair causes double strand breaks and mutation induction

Effector functions of different Ig

(Ig types and responses triggered)

• IgG1 - classical complement activation, placental transfer, low affinity binding to phagocytes, high affinity binding to macrophages and activated neutrophils
• IgG2 - some complement activation, placental transfer
• IgG3 - classical complement activation, placental transfer, low affinity binding to phagocytes, high affinity binding to macrophages and activated neutrophils
• IgG4 - placental transfer and some high affinity binding to macrophages and activated neutrophils
• IgA - low affinity binding to phagocytes
• IgE - low affinity binding phagocytes and high affinity binding to basophils and mast cells

CD4 cell differentiation and functions

(cell type, APC cytokine release, TFs, cytokine/receptor production, response mediated)

• Interaction with APC cell through antigen bound MHC-II-TCR combined with specific cytokine release induces maturation and differentiation of CD4 T cells
• Th1 - Release of IL-12 induces STAT4 and T-vet TFs. Expression of IL-12R and IFN-γR, release of IFN-γ and TNF-α, mediating cell-mediated immunity against intracellular bacteria and viruses
• Th2 - release of IL-4 induces STAT6 and GATA3. Expression of IL-4R and release of IL-4, IL-5 and IL-13, mediating humoral immunity against extracellular parasites
• Th17 - release of TGF-β and IL-6 induces STAT3 and RORγt. Expression of TGF-β1R and IL-23R and release of IL-17A, IL-17F and IL-22, mediating cell-mediated inflammation, autoimmune diseases and response to extracellular pathogens and fungi
• Treg - release of TGF-β induces Foxp3. Expression of IL-2R and TGF-β1R and release of TGF-β and IL-10, mediating immunoregulation and peripheral tolerance
• Thf - release of IL-6 and IL-21 induces BCL6. Expression of IL-21R and release of IL-21, IL-4 mediates B cell help

Immunoprivilege

(sites and mechanisms)

• Sites - brain, eyes, placenta, testes, articular cartilage (to some extent)
• Mechanisms - lack of lymphatic drainage, low MHC-I expression, expression of immunoregulator MHC-Ib receptors, increased expression of complement inhibition proteins, production of anti-inflammatory cytokines, presence of neuropeptides, expression of Fas ligand to kill Fas-expressing lymphoid cells

• CD8 cells - release of perforin which binds to plasma membrane and oligomerises to form pores on target cell membrane. Pores then allow the introduction of granzymes which trigger caspase cascade via serine protease function resulting in apoptosis. Granulysin is also involved in pore formation of infected cell membrane
• Fas-L pathway - activation causes expression of FAS ligand which binds Fas. This recruits recruitment of death-induced signalling complex (DISC) which translocated with the Fas-associated death domain (FADD) to facilitate the recruitment of procaspases 8 and 10. This subsequently activates caspases 3,6 and 7 to cleave lamin A, B1/2, PARP and DNAPK to allow cell apoptosis
• NK cells - receptors - Ly49, CD94, NKG2 (lectins) identifies MHC-I molecules 
• Release of cytolytic granules (as CD8). Also release of α-defensin to allow direct bacterial killing
• Opsonisation of pathogens - release of cytolytic granules from NK cells
• Cytokines (IL-12, 15,18,2 and CCL5) trigger NK activation, while they themselves release IFNγ and TNFα - allows immediate viral protection by macrophage activation
• Surveillance of cells not expressing Fas - mechanism by many viruses to prevent cell death