Diseases Of The Immune System Flashcards
What are the six major components of the innate immune system?
- Epithelia
- Monocytes and neutrophils
- Dendritic cells
- Innate lymphoid cells
- Other cell types e.g. mast cells
- Plasma proteins e.g. complement proteins
Mammals have 10 Toll-like receptors, each recognising a different set of microbial molecules. They are found in the plasma membrane and endosomal vesicles. What is the result of the common pathway they signal by?
- Activation of transcription factor NF-kB which stimulates synthesis and secretion of cytokines and the expression of adhesion molecules
- Activation of interferon regulatory factors which stimulate the production of the antiviral cytokines, type I interferons
Several NOD-like receptors (found in cytosol) signal via a multiprotein complex, the inflammasome, which activates caspase-1 which in turn activates IL-1. What can trigger this pathway?
- Products released from damaged/necrotic cells e.g. uric acid, ATP
- Loss of intracellular K+
- Some microbial products
For the following receptors relating to innate immunity, identify their cellular location, and the type of substances they respond to:
1. C-type lectin receptors
2. RIG-like receptors
3. Receptors that activate the STING pathway (leading to production of interferon-a)
4. G-protein coupled receptors
5. Mannose receptors
- Plasma membrane of macrophages and dendritic cells. Fungal glycans
- Cytosol of most cell types. Viral nucleic acids
- Cytosol. Microbial DNA (often viruses)
- Plasma membranes of neutrophils, macrophages and most lymphocytes. N-formylmethionine (all bacterial proteins initiated by this)
- Plasma membranes of phagocytes. Microbial sugars (which often contain terminal mannose residues)
What is the role of natural killer cells?
To recognise and destroy severely stressed or abnormal cells.
note also secrete cytokines like interferon-y, activating macrophages to destroy ingested microbes
The binding of CD16 on NK cells with IgG Fc tails is what ultimately confers the ability to lyse the target cell (antibody-dependent cellular cytotoxicity). This is regulated by activating and inhibitory receptors also, what expressed molecules could affect these?
Surface molecules induced by stress (activating), self class I MHC molecules, expressed on all healthy cells (inhibitory)
What reactions of the innate immune system allow it to provide host defence?
Inflammation, antiviral defence, stimulate the adaptive immune response.
What are the two types of adaptive immunity and the cell types that mediate them?
Humoral immunity - B lymphocytes
Cellular immunity - T lymphocytes
What is the enzyme responsible for recombining antigen receptor genes in B and T cells?
RAG proteins (products of RAG-1 and RAG-2)
What are the three major populations of T cells and their basic function?
- Helper T lymphocytes - stimulate B lymphocytes to make antibodies and activate other leukocytes to destroy microbes
- Cytotoxic T lymphocytes - kill infected cells
- Regulatory T lymphocytes - limit immune responses and prevent reactions against self antigens
alpha/beta T cell receptors can recognise antigens under what circumstance?
(gamma/delta TCRs do not need this, found on a small population of lymphocytes)
When they are presented on major histocompatibility (MHC) molecules on antigen presenting cells.
What proteins form the TCR complex?
The alpha and beta polypeptide chains of the TCR, six noncovalently linked chains comprising the CD3 complex and (greek)s chain dimer
CD4 and CD8 both act as coreceptors in T cell activation. What are the differences between them?
CD4 - binds only to class II MHC molecules and found on T helper cells
CD8 - binds only to class I MHC molecules and found on cytotoxic T cells
After stimulation of the B cell receptor complex B cells develop into plasma cells and memory B cells. what is the B cell receptor complex made of?
An IgM or IgD antibody and a heterodimer of Iga (CD79a) and Igb (CD79b)
On B cells where do CR2(CD21) and CD40 receptors get signals from respectively?
Complement products and helper T cells
What are four features of dendritic cells that account for their key role in antigen presentation?
- Location (under epithelia and in the interstitia of all tissues)
- Expression of many receptors for capturing and responding to microbes (and other antigens), including TLRs and lectins
- In response to microbes they are recruited to the T cell zones of lymphoid organs to present antigens to naïve T cells
- Express high levels of MHC and other molecules needed for antigen presentation and T cell activation
What are the secondary lymphoid organs?
Lymph nodes, spleen, mucosal and cutaneous lymphoid tissues
What is the general structure of lymph nodes as an example of the segregation of naïve B and T lymphocytes?
B cells are concentrated in discrete follicles around the periphery, along with FDCs. These may have a germinal centre if B cells within one have recently responded to an antigen.
T lymphocytes are concentrated in the paracortex, adjacent to the follicles with DCs.
Where can T lymphocytes and B lymphocytes be found in the spleen respectively?
- Periarteriolar lymphoid sheaths
- Follicles in areas known as the splenic white pulp
MHC molecules class I and II, also called HLA in humans are encoded by what genes from what chromosome?
From the MHC locus on chromosome 6
MHC class I alpha chain by HLA-A, HLA-B and HLA-C
MHC class II from the HLA-D region by HLA-DP, HLA-DQ and HLA-DR
Both class I and II MHC molecules are noncovalently linked heterodimers with highly variable alleles in the population affecting affinity of binding to different peptides.
Compare their structures.
- Class I - Polymorphic alpha or heavy chain with three domains - a3 is nonpolymorphic and is the site of CD8 binding. Once bound to a cytoplasmic peptide (between a1 and a2) will associate with B2-microglobulin chain to form the stable complex then transported to the cell surface.
- Class II more equally sized alpha and beta chains, both polymorphic. Peptides (antigens derived from extracellular microbes or proteins) bind at the interaction face of a1 and B1. B2 binds CD4
What leads to the largely unique HLA haplotype in an individual?
Inheritance of one set of HLA genes from each parent. Then expression of different molecules for each gene locus. This plus the significant polymorphism of HLA genes leads to two unrelated individuals expressing the same HLA halotype being extremely unlikely. For siblings it is 1 in 4.
What are two different types of immune response, and two other immune requirements cytokines contribute to?
Innate (TNF, IL-1, IL-12 type I IFNs, IFN-y), adaptive (IL-2, IL-4, IL-5, IL-17, IFN-y), termination (TGF-B, IL-10) and stimulation of hematopoiesis to increase leukocyte production (CSFs and IL-3)
What is the overall function of cytokines in the innate and adaptive immune responses respectively?
- To induce inflammation and inhibit virus replication
- Promote lymphocyte proliferation and differentiation as well as to activate effector cells.
Costimulation of the adaptive immune response is important to ensure it is not directed at harmless antigens. What are the principal costimulators for T cells, and the receptor they act on?
B7 proteins (CD80 and CD86) on antigen presenting cells recognised by CD28 on naïve T cells
What is one of the earliest responses of a CD4+ helper T cells once activated?
Secretion of IL-2 and expression of high affinity receptors for IL-2 creating an autocrine loop where IL-2 acts as a growth factor stimulating T-cell proliferation.
Some CD4+ T cells differentiate into effector cells which secrete distinct sets of cytokines. For Th1, Th2 and Th17 what are these and what is their function?
- Th1 - IFN-y, potent ‘classical’ macrophage activator along with CD40L
- Th2 - IL-4, stimulates B cell differentiation into IgE plasma cells, and T cells to Th2. IL-5, stimulates eosinophil production and activates them at immune response sites. IL- 13 enhances IgE production and stimulates epithelial mucus secretion. Also induce ‘alternative’ macrophage activation.
- Th17 - IL-17, recruits neutrophils and monocytes
What are the two pathways by which antibody responses to antigens are triggered?
- T-dependent - B cells endocytose antigens recognised by Ig receptors and display degraded peptides from these on MHC class II molecules, activating helper T cells which recognise these, causing them to express CD40L and cytokines, in turn stimulating B cells.
- T-independent - When polysaccharide and lipid antigens that can’t bind to MHC molecules engage antigen receptor molecules on B cells, activating them. This tends to be a relatively simple response, stimulating secretion of mainly IgM antibody.
What is the function of T follicular helper cells?
Stimulate activated B cell affinity maturation and isotype switching as well as proliferation within germinal centres in follicles.
As well as binding microbes preventing them from infecting cells, which antibodies;
1. Opsonise, targeting for phagocytosis?
2. Activate the complement system by the classical pathway?
3. Cooperate with eosinophils to kill parasites?
4. Is secreted by mucosal epithelia?
5. Is actively transported across the placenta?
- IgG
- IgG and IgM
- IgE
- IgA
- IgG
What is the half life of most IgG antibodies?
3 weeks
Where can plasma cells actively (continuing antibody production) reside for months to years?
Bone marrow
Characterise the two phases of a local type I hypersensitivity reaction
- Initially vasodilation, vascular leakage and depending on the tissue smooth muscle spasm or glandular secretions.
- 2-24 hours later (late phase), infiltration with eosinophils, neutrophils, basophils, monocytes and CD4+ T cells with tissue destruction, typically mucosal epithelial damage
What are the four types of hypersensitivity reactions?
- Type I - Immediate hypersensitivity
- Type II - Antibody-mediated hypersensitivity
- Type III - Immune complex-mediated hypersensitivity
- Type IV - Cell-mediated hypersensitivity
The excessive response of what cell type causes most immediate hypersensitivity disorders?
Th2
Mast cells can be activated by a number of triggers such as C5a, C3a, IL-8, codeine, morphine, adenosine, melittin and IgE. How does activation via IgE antibodies work?
FceRI is a high affinity receptor specific for Fc of IgE. A mast cell is sensitised when it is coated with IgE. Multivalent antigens bind and cross link IgE bringing Fce receptors together, triggering signal transduction pathways that lead to release mediators and production of others
Give examples of the mediators of immediate hypersensitivity that are released from mast cell granules under the categories of 1. Vasoactive amines, 2. Enzymes, 3. Proteoglycans
- Histamine (smooth muscle contraction, increases vascular permeability, stimulates mucus secretion.
- Neutral proteases (chymase, tryptase) and acid hydrolases. (Tissue damage, kinin generation and activation of complement)
- Heparin and chondrotin sulfate
Other than those released by granules, what other mediators do mast cells release during a hypersensitivity reaction?
- Lipid mediators (Leukotrines, protoglandin D2, PAF)
- Cytokines (TNF, IL-1, chemokines, IL-4)
What is often an abundant leukocyte population in a late phase hypersensitivity reaction and what do they do?
Eosinophils - Liberate proteolytic enzymes and major basic protein and eosinophil catinoic protein, causing tissue damage. Sometime release Charcot-Leyden crystals (galectin-10) which promote inflammation and enhance Th2 response.
Name four examples of disorders caused by immediate hypersensitivity
Anaphylaxis, Bronchial asthma, allergic rhinitis, food allergies
What are the three mechanisims by which antibody-mediated hypersensitivity can cause disorder?
Opsonisation and phagocytosis (when affects cells), inflammation (when affects fixed tissues) and cellular disfunction
What are four examples of disorders caused by antibody-mediated hypersensitivity acting through opsonisation and phagocytosis?
- Transfusion reactions
- Haemolytic disease of the newborn
- Autoimmune haemolytic anaemia/agranulocytosis/thrombocytopenia
- Drug-induced destruction of blood cells
Type II hypersensitivity reactions caused through inflammation occur due to the antibodies activating the complement cascade in turn triggering the rest of the inflammatory mediators, damaging the affected tissues. What are some examples of disorders caused by this?
Some forms of glomerulonephritis and vascular rejection in organ grafts.
In some cases of type II hypersensitivity reactions antibodies directed against cell surface receptors can affect their function without causing cell injury or inflammation. What are two examples of this?
- Myasthenia Gravis - reactive with acetylcholine receptor in the motor end plates of skeletal muscles. block transmission therefore causing weakness
- Graves disease - against TSH receptors on thyroid epithelial cells. stimulating the cells, resulting in hyperthyroidism
What are the three phases of the pathogenesis of systemic immune complex-mediated hypersensitivity disorders?
- Formation of immune complexes of antibodies and antigen (about 1 week after first exposure)
- Deposition of immune complexes in vessels - organs where blood is filtered at high pressure to form other fluids, like urine and synovial fluid, are sites where these complexes become concentrated and tend to deposit
- Inflammation and tissue injury (about 10 days post exposure) (acute, antibody mediated with high complement and neutrophil involvement- can cause fibrinoid necrosis)
What are some examples of immune complex-mediated hypersensitivity diseases?
Serum sickness, SLE, reactive arthritis, poststreptococcal glomerulonephritis. Arthus reaction (experimental)
Initial differentiation of CD4+ T cells is driven by the cytokines produced by the APC at the time of T cell activation. Which will produce Th1 and Th17?
- Th1 IL-12 (then self amplified with IFN-y)
- Th17 IL-1, IL-6 and IL-23
What is the prototype of CD4+ T cell-mediated hypersensitivity inflammation?
Delayed type hypersensitivity, e.g. the tubercillin reaction, contact dermatitis
What is delayed-type hypersensitivity morphologically characterised by?
accumulation of mononuclear cells, mainly CD4+ T cells and macrophages, around venules producing perivascular “cuffing”. In fully developed lesions the venules show marked endothelial hypertrophy (reflecting cytokine mediated activation)
