Immunology Flashcards
What cell type expresses CD20 and CD19?
Late pro-B-cells through to memory B-cells, but not plasma cells.
What cells express CD38 and CD135?
Plasma cells. They also express a marker called plasma cell antigen 1. Note that early stage B cells also express 38, but that they don’t get it back until they become plasma cells, and the early B-cells don’t express CD135. Daratumumab is a monoclonal ab that targets CD38 and is used to treat multiple myeloma by attacking monoclonal (and all other) plasma cells.
What cells express CD44?
Mature, and some early stage, CD4 and CD8 helper t cells.
What are 3 signals needed to prime a naive T-cell?
- Antigen specific TCR activation. 2. Interaction with costimulatory molecules on APCs with T-cell ligands and 3. Cytokines which guide the differentiation of the T-cell
What is chemokine receptor 7 (CCR7)?
Recall that chemokines are molecules that guide the movement of cells down a concentration gradient. CCR7 binds to CCL21, which is released from peripheral lymphoid tissue. Naive T-cells use CCR7 to find lymphoid tissue and look for their antigen. Tissue dendritic cells suddenly express CCR7 after their TLRs encounter PAMPs.
What does T-cell membrane bound protein LFA-1 bind to? Why is it significant?
LFA-1 binds to APC ICAM-1 and ICAM-2. If TCR - antigen - MHC binding occurs simultaneously, the LFA-1 protein undergoes a conformational change that causes the cells to stay bound for several days to a allow for T-cell clonal proliferation.
What’s important about B7 and CD28 with regard to T-cells?
B7 is expressed exclusively on the surface of APCs able to prime T-cells once the APC is activated (i.e. has antigen to display). B7 binds to CD28 on naive T-cells and is necessary for naive T-cell priming. When bound it stimulates the production of IL-2 and a high-affinity version of the IL-2 receptor by the T-cell. Autocrine IL-2 activity pushes the T-cell back into its cell cycle to replicate.
What does IL-2 do? Hint, it’s part of an autocrine system.
Once co-stimulatory molecules B7 on APCs and CD28 on naive T-cells occurs AND a corresponding MHC+antigen+TCR complex is formed, the T-cells upregulate the production of IL-2 and the high-affinity IL-2 receptors to self-propel clonal expansion and differentiation. Once differentiated IL-2 is also vital to keeping effector cells alive- in the absence of IL-2, effector T-cells die.
What happens downstream after a naive T-cell receptor binds with its antigen and an MHC complex on an APC? What drugs work here?
Of most relevance here is that tacrolimous and Cyclosporin A work by indirectly inhibiting calcineurin and preventing the dephosphorylation of NFAT- markedly impacting T-cell IL-2 and IL-2 receptor manufacture, and thus inhbiting T-cell proliferation and contributing to effector T-cell death.
What is the role CTLA-4? What drugs inhibit it?
In peripheral lymphoid tissue, CTLA-4 is expressed on cells to compete with the binding of naive T-cells to B7, the costimulatory molecule present on activated APCs. It binds much more readily to B7 than CD28. In this way, it down regulates proliferation T-cells. It is also expressed on T-cells after they have been primed, so as to slow the costimulation of itself and neighbouring cells in lymphoid tissue. Ipilimumab inhibits CTLA-4 to enhance the immune response when treating cancer. It is used in renal cancers and melanoma.
JAK/STAT - what is this really?
Janus (a Roman God with 2 heads) kinase/signal transducers and activators of transcription. JAKs are the intracellular domains of many cytokine receptors and are part of the tyrosine kinase group. Each JAK intracellular domain head/cytokine receptor has a corresponding JAK intracellular domain head/cytokine receptor. When a cytokine is present, the 2 parts of the cytokine receptor extracellularly, and the two JAKs intracellularly, interact through phosphorylation causing them to bind a specific STAT (also two parts) which when activated is able to enter the nucleus to directly influence transcription.
What is the primary role of cascades?
They are the effectors of apoptosis- whether activated intrinsically or extrinsically. They systematically deconstruct the cell.
What’s the mechanism of endogenous in the setting of infection fever?
Macrophages and dendritic cells produce IL-6, IL-beta and TNF-alpha in response to pathogens and to a lesser extent, tissue damage. There cytokines induce the production of protstaglandin E2. Circulating PE2 causes the hypothalamus to increase sympathetic activity body-wide. This leads to systemic vasoconstriction, brown fat increases heat production and piloerection and rigoring maintain and generate heat respectively.
Activated macrophages and dendritic cells produce a number of important chemokines at drive the immediate response to infection. What are they?
IL-1beta
TNF-alpha
IL-6
CXCL8 (chemokine)
IL-12
What does IL-1beta do? What produces it?
Produced by activated macrophages and conventional dendritic cells. Locally, IL-1beta activates vascular endothelium, activates lymphocytes, causes local tissue destruction, increases access of effector cells to site of infection. Systemically, IL-1Beta causes fever and stimulates other cells to produce IL-6.
What does TNF-alpha do, and what produces it?
Produced by activated macrophages and conventional dendritic cells, TNF-alpha is the main driver of shock in sepsis as it activates vascular endothelium increasing tissue permeability with the goal of allowing better immune component access to sites of infection. Binding to TNFR-1 in some cells (e.g. lymphocytes) leads to pro-inflammatory responses, and in others leads to cell death via apoptosis. TNFR-2, expressed on T-cells, always leads to activating gene transcription.
What is IL-6, and what does it do?
IL-6 is produced by activated macrophages and conventional dendritic cells. It contributes to lymphocyte activation and increases antibody production locally, and systemically causes fever, induces the production of acute phase reactants — CRP, MBL, surfactants SP-A and SP-D, fibrinogen and serum amyloud protein.
What drugs target TNF-alpha? What diseases are they effective against? What risks should be consideted before commencing these medications?
TNF-alpha antagonists have been successful in the treatment of rheumatoid arthritis, ankolysing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis and Crohns disease. Anti-TNF-alpha abs are inflixamab, adalimumab, cetrolizumab and golilimumab. Decoy receptor for TNF-alpha is entanercept. Notable risk is tuberculosis reactivation. Notable autoinflammatory disease they don’t work in is MS.
What’s Fas and Fas ligand?
Fas is expressed on many cells. When in contact with its ligand (which can happen for many reasons), it activated apoptosis. Mutations in Fas or its downstream caspases leading to loss of function cause Autoimmune Lymphoproliferative Syndrome due to the failure of controlled death of lymphocytes.
What is the role of plasmacytoid dendritic cells?
In response to viruses they produce 1000x more type 1 interferons (alpha and beta) than other cells. Also after typing up virus particles, they express chemokine receptors that guide them to lymph nodes to allow them to influence naive lymphocytes. They also produce CD40 ligand, which binds to CD40 on conventional dendritic cells and perpetuates the production of IL-12, stimulating further the production of interferon gamma and enhancing macrophage killing potential.
What are the type 1 interferons, and what do they do?
Interferon-alpha (a subfamily of related proteins) and interferon-beta (a single protein that stimulates the production of interferon-alpha) are produced by almost all cells in response to virus. Plasmacytoid dendritic cells pros at doing this though- making 1000x more than other cells when encountering virus. Group 1 interferons via the interferon receptor—JAK/STAT pathway induce the production of Mx proteins thay interfere with viral replication, oligoadenylate synthetase which alters viral RNA to make it non-functional, and increase the expression of MHC-I in all cells. They also activate macrophages, conventional dendritic cells and NK cell, and induce chemokine production to recruit lymphocytes to sites of infection.
What are the type 1 interferons, and what do they do?
Interferon-alpha (a subfamily of related proteins) and interferon-beta (a single protein that stimulates the production of interferon-alpha) are produced by almost all cells in response to virus. Plasmacytoid dendritic cells pros at doing this though- making 1000x more than other cells when encountering virus. Group 1 interferons
What is the role of natural killer cells, how are they activated, and how do they do their work?
They are responsible for the early control of viruses and killing cancer cells. They are activated by type 1 interferons (produced largely by activated plasmacytoid dendritic cells) or IL-12 (produced by activated macrophages or conventional dendritic cells). They enzymatically destroy any cell that doesn’t produce adequate MHC-I, or produce altered MHC-I - a common strategy employed by cancer cells or virus infected cells to avoid detection by CD8 Tcells. Other signals shift the balabce towards killing such as the presence of Fc regions on target cells. In response to IL-12, NK cells produce interferon gamma. Pts with dysfunctional NK cells are susceptible to frequent recurrence of chronic viral infections like HZV and CMV.
What’s the difference between the CD8 T-cell responses to tumour or viruses?
Conventional dendritic cells can unilaterally activate naive CD8 cells to proliferate into effector cells to attack cancer cells. To destroy virus infected cells however, CD8 activation usually requires costimulation from an APC AND a CD4 T cell with the same antigen specific TCR. Dendritic cells when simultaneously bound to activated virus antigen specific CD4 T cells and naive CD8 T cells stimulate the CD4 T cells to produce CD40 ligand and IL-2. CD40L binds to the CD40 receptor on the dendritic cell and leads to production of more B7 receptors to bind more CD28 on T-cells, and a ligand called 4-IBBL that binds to 4-IBB on CD8 T cells to accelerate their growth. The IL-2 production from helper T cells also drives the nearby CD8 cells to activate.
A naive CD4 T cell encounters its antigen in the presence of IL-6 and and TGF-beta. The milieu does not contain IL-4 or IL-12. What does it differentiate into?
A Th17 Helper T-cell. In the first step, IL-21 is produced by naive CD4 T cells in response to IL-6 and TGF-beta. IL-21 in an autocrine manner drives, via a JAK-STAT receptor, complete differentiation to Th17 cell which express IL-23 receptors. IL-23 exposure it was drives their expansion. Th17 cells produce IL-17 once mature.
What does IL-17 do?
Produced by Th17 cells, IL-17 indirectly promotes inflammation. It causes local stomal and epithelial cell to produce chemokines that attract neutrophils.
What interleukin is required for differentiation from naive CD4 T cells to Th2 cells?
IL-4 drives the maturation in to Th2 cells, which subsequently produce abundant IL-4/9/13 and 5. The initial IL-4 is likely from activated mast cells or eosinophils.
During infection with extracellular bacterial or fungus, macrophages produce TNF-alpha, IL-6 and IL-1 beta. Dendritic cell produce IL-6 and IL-23. This cytokine mileu leads to maturation of Helper T cells to what subtype?
Th17 cells. Important for the production of IL-17 which induce the production of local chemokines by fibroblasts and epithelial cells to attract more WBCs to the site of infection as well as produce GM-CSF and G-CSF to stimulate the production of and attract more neutrophils and macrophages to the site of infection. Th17 cells also produce IL-22 which causes keratinoctes to produce beta defensins and other antimicrobial agents. Th17 cells are critical to protecting the interface between self antigens and commensal organisms from pathogenic organisms. Ustekinumab targets IL-23/IL-12 to counter the effects of Th17 cells as well Th1 cells respectively.
Which cells express CD40 ligand, and what does it do?
Expressed by Th2, Th17, Th1 and Tfh cells. Binds to CD40 on B-cells to provide cognate help to activate them and initiate isotope switching. Also binds CD40 on macrophages, causing to make more TNF-alpha and be activated more easily.
