What are functions of the macrophages?
Broadly they eliminate injurious agents (eg. microbes) and initiate repair.
- Macrophages phagocytose microbes and dead tissue
- Initiate tissue repair, scar formation and fibrosis
- Contribute to the initiation and propagation of inflammation by secreting mediators of inflammation such as cytokines (TNF, IL-1, chemokines and others) and eiconsanoids
- Induce cell-mediate immune response by displaying antigens to T lymphocytes.
What are the two major pathways of macrophage activation and explain?
Classic and Alternative pathway
Classic pathway (M1 Macrophages)
- Activation by endotoxins (TLR and other sensors), T-cell-derived signals, IFN-y, foreign substances
- Produce NO and lysosomal enzymes to eliminate organism and secrete cytokines (IL-1, IL-12, IL-23, chemokines) that stimulate inflammation
Alternative pathway (M2 Macrophages)
- Induced by IL-4, IL-13 (cytokines produced by lymphocytes and other cells)
- Functions to terminate inflammation (IL-10 and TGF-B) and promote tissue repair (Growth factors, TGF-B)
What are the different types of CD4+ T lymphocytes and function?
There are three subsets of CD4+ T lymphocytes:
1. Th1 cells: produce IFN-y which actives macrophages by the classical pathway
2. Th2 cells: secrete IL-4, IL-5, IL-13 which recruits and activates eosinophils and responsible for activation of the alternative pathway of macrophages (M2).
3. Th17 cells: secrete IL-17 and other cytokines which induce the secretion of chemokines responsible for recruiting neutrophils (and monocytes) in the reaction.
Which CD4+ T lymphocytes are responsible for defense against bacteria and viruses, as well as, autoimmunity?
Th1 and Th17
Which CD4+ T lymphocytes are responsible for defense against helminths, parasites and allergic inflammation?
Th2
What are the regulatory proteins of the complement system?
- C1 inhibitor (C1 INH)
- Decay accelerating factor (DAF) and CD59 (plasma membrane proteins anchored by GPI)
- DAF prevents formation of C3 convertase
- CD59 inhibits formation of membrane attack complex - Complement Factor H (circulating glycoprotein) - inhibit the alternative pathway by promoting cleavage and destruction of C3b and turnover of the C3 convertases.
What is the effects of activated Toll-like receptors (TLRs)?
Activation of (2) transcription factors:
1. NF-kB: Stimulation of synthesis and secretion of cytokines and expression of adhesion molecules
- Interferon regulatory factors (IRFs): Stimulates the production of antiviral cytokines, Type I Interferon
What is the effect of activated NOD-like receptors?
Downstream signals via inflammasomes (cytosolic multiprotein complex) which actives caspase-1 that cleaves a precursor of IL-1 and form IL-1 active form.
What actives Toll-like receptors?
Pathogen-associated molecular patterns (PAMPs) and Damage-associated molecular patterns (DAMPs)
What immune receptor detects fungal glycans and where are they found?
C-type lectin receptors (CLRs) expressed on plasma membrane of macrophages and dendritic cells.
- Elicit a inflammatory response to fungi
What are RIG-like receptors?
(i) Where are they located?
(ii) What do they detect?
(iii) What effects do they cause?
RIG-like receptors (retinoid acid inducible gene I)
Located: cytosol of most cell types
Detect: Nuclei acids of viruses that replicate in the cytoplasm of infected cells
Effects: Activate STING pathway (for stimulator of interferon gene) which leads to the production of antiviral cytokine interferon-alpha
What immune receptor recognizes short bacterial peptides containing N-formylmethionyl residues?
(i) What cells are they found in?
(ii) What effects do they produce?
G-coupled proten receptors
Found on neutrophils, macrophages and most ther types of leukocytes
Effects: Chemotaxis
What receptors recognize microbial sugars?
(i) Why do they function as immune receptors?
(ii) What effects do they produce?
Mannose receptor
Why: Microbial sugars often contain terminal mannose residues, unlike mammalian glycoproteins
Effect: Induce phagocytosis of microbes
What is the function of natural killer cells (NK cells)?
Recognize and destroy severely stressed or abnormal cells.
Eg. Tumour cells and virus-infected cells
Which receptors (CD) are on natural killer cells and what do they do?
CD-16
Allows NK-cells to bind to IgG Fc tail giving the cells the ability to lyse IgG-coated target cells. This phenomenon is called antibody-dependent cellular cytotoxicity.
How is killing of target cells by Natural Killer cells regulated?
It is regulated by activating and inhibitory signals.
Activating signals - many types (not listed)
Inhibitory signals: class I MHC (major histocompatibility complex) is found on all healthy cells
Infected cells, cells with DNA damage or neoplastic cells often enhance expression of ligands for activating receptors and simultaneously reduce the expression of class I MHC molecules. This balance shifts towards activation and the cell is killed.
How do Interleukins affect Natural Killer cells?
IL-2, IL-15: stimulates the proliferation of NK cells
IL-12 actives the killing of target cells and the secretion of IFN-y
What are the types of adaptive immunity?
There are two types:
1. Humoral immunity is mediated by B-lymphocytes which secrete antibodies
- This is responsible for extracellular microbes and cancer
- Cellular immunity is mediated by T-lymphocytes
What is clonal selection?
Lymphocytes specific for a large number of antigen exist before exposure to antigen, and when an antigen appears it selectively activates the antigen-specific cells.
How do lymphocytes produce antigen receptor diversity?
Antigen receptor diversity is generated by somatic recombination of the genes that encode antigen receptors. All cells of the body, including lymphocyte progenitors contain antigen receptor genes in the germline configuration, in which the genes encoding these receptors consists of spatially separated segements that cannot be expressed as mRNAs. During lymphocyte maturation these gene segments are assembled by recombination and DNA sequence variation is introduced at the site where the gene segments are joined. The enzyme in developing lymphocytes that mediate recombination of these gene segment is the product of RAG-1 and RAG-2 (recombination-activating genes, Chr 11p13). Only T and B cells contain recombined antigen receptor genes.
What are the different types of T-lymphocytes and their function?
There are three major populations of T-cells:
1. Helper T-cells: Stimulate B lymphocytes to make antibodies and active other leukocytes to destroy microbes
2. Cytotoxic (Killer) T lymphocytes (CTL): Kill infected cells
3. Regulatory T-cells: limit immune response and prevent reaction against self antigen
State which MHC class receptors binds to TCR of CD4+ and CD8+ T cells
CD4+ T cells bind to MHC class II
CD8+ T cells bind to MHC class I
What percentage of lymphocytes constitute T cells and B cells respectively?
T-cells: 60 - 70%
B-cells: 10-20%
What percentage of T-lymphocytes are CD4+ vs CD8+-T-Cells?
Approximately 60% are CD4+ T-cells and 30% are CD8+ T-Cells
