Chapter 6: Diseases of the Immune System Part 1 Flashcards
What are the major components and cells of the innate immunity?
- Epithelial barriers
- Phagocytic cells (neutrophils and macrophages)
- DCs
- NK cells
- Complement proteins
How is complement system activated in innate vs. adaptive immune response?
Innate: microbes using the alternative and lectin pathways
Adaptive: by antibodies using the classical pathway (GM makes classic cars)
Which cells involved in the initiation of the innate immune response?
Dendritic cells
Function of mannose-binding lectin and C-reactive protein in the innate immune response?
Coat microbes and promote phagocytosis
What are examples of plasma proteins in the innate immune response?
- Complement
- Mannose-binding lectin and CRP
- Lung surfactant
What cells provide early protection against viruses and intracellular bacteria?
Nk cells
What are the plasma membrane PRRs used to detect extraceullar microbes?
What does each detect?
- TLR = bacterial products
- C-type Lectin receptor (CLRs) = microbial polysaccharides
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TLRs present in the plasma membrane and endosomal vesicles signal via a common pathway that leads to activation of what 2 sets of transcription factors?
1) NF-kB, stimulates synthesis and secretion of cytokines and expression of adhesion molecules, both critical for recruitment and activation of leukocytes
2) Interferon regulatory factors (IRFs), which stimulate production of antiviral cytokines, type I interferons
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Where are NOD-like receptors found and what do they recognize?
- Cytosolic receptors
- Recognize products of necrotic cells like uric acid, ATP, ion disturbances (i.e., loss of K+), and some microbial products
Several NOD-like receptors (NLRs) signal via which cytosolic multiprotein complex, which activates?
Gain of functon mutations in one of NLRs results in?
How are these mutations treated?
- NLRP3 (sensor) of Inflammasomewhich activatescaspase-1that cleavespro-IL-1β to its active form.IL-1β involved in recruitment of leukocytes and induction offeverduringacute inflammatory process
- Gain-of-function mutations result in periodic fever syndromes, called autoinflammatory syndromes
- Respond well to IL-1 antagonists
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NLR-inflammasome pathway may play a role in what disorders?
- Recognition of urate crystals by class of NLRs underlies inflammation in Gout
- Obesity-associated type 2 diabetes (recognition of lipids deposited in tissues)
- Atherosclerosis (recognition of cholesterol crystals)
C-type lectin receptors are expressed where?
Detect what?
- Plasma membrane of macrophages and DCs
- Detect fungal glycan and elicit inflammatory rxns to fungi
RIG-like receptors are located where and detect what?
Stimulate production of?
- Located in cytosol
- Detect nucleic acids of viruses that replicate in the cytoplasm
- Stimulate production of antiviral cytokines
GPCRs located on what immune cells and recognize?
- Neutrophils, macrophages, and most other types of leukocytes
- Recognize short bacterial peptides containing N-fMet
Somatic recombination which generates Lymphocyte diversity in both the thymus and bone marrow is mediated by what enzyme/genes?
Mutation of these genes results in?
- Enzyme product of RAG-1 and RAG-2 (recombinant activating genes)
- Failure to generate mature lymphocytes
What are the recombined (aka rearranged) antigen receptors found on B and T cells?
B cell = Ig
T cells = TCR
How is analysis of antigen receptor gene rearrangements a valuable assay for detecting lymphomas?
How is this done?
- Moleulcar assays using PCR can determine if a lymphocyte proliferation is polyclonal (non-neoplastic)ormonoclonal (neoplastic)
- Each T or B cell and its clonal progeny have a unique DNA rearrangement (and hence unique antigen receptor)
95% of the TCRs are heterodimers consisting of what kind of chain?
Recognize Ags how?
- Consist of α and β polypeptide chains
- Recognize Ags presented by MHCs on surface of APCs
Small population of mature T cells contain a γδ TCRs which recognizes?
Tend to aggregate where?
- Recognize peptides, lipids, and small molecules WITHOUT assistance from MHC proteins
- Aggregate at epithelial surfaces, such as the skin and mucosa of GI and Urogenital tract
NK-T cells recognize what?
Glycolipids displayed by MHC-like molecule CD1
Cytokine-secreting helper cell that assists macrophages and B lymphocytes to combat infections describes what cell type?
CD4+ T cells
Which Ig’s present on the surface of all mature, naive B cells are the antigen-binding component of the B-cell receptor complex?
IgM and IgD
What heterodimer of invariant proteins is found on the B-cell antigen receptor and are essential for signal transduction?
What are other important molecules are expressed on B cells that are essential for their responses?
- Igα (CD79a) and Igβ (CD79b) essential for signal transduction
- Type 2 complement receptor (CR2 or CD21) recognizes complement products generated during innate response
- CD40 receives signals from helper T cells
Epstein-Barr virus (EBV) can use which receptor to enter and infect B cells?
CR2 (type 2 complement receptor)
Where are follicular DCs found?
What kind of receptors do they have, which allows them to do what?
Play a role in which immune response and how?
- Germinal centers of lymphoid follicles in spleen and LNs
- Have Fc receptors for IgG and receptors for C3b = can trap Ag bound to Ab’s or complement proteins
- Play role in humoral immune response by presenting Ags to B cells and selecting B cells that have the highest affinity = improving quality of antibody produced
What are 3 important functions of macrophages?
- Function as APCs in T-cell activation
- Key effector cells in certain forms of cell-mediated immunity. T cells activate macrophages and enhance their ability to kill ingested microbes
- Participate in effector phase of humoral immunity, by efficient phagocytosis and destruction of opsonized (coated) microbes by IgG or C3b
NK cells contain abundant?
What 2 cell surface molecules are commonly used to identify NK cells?
- Abundant azurophilic granules
- CD16 and CD56
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Which cells function to destroy irreversibly stressed and abnormal cells, such as virus-infected and tumor cells?
Natural Killer (NK) Cells
Function of CD16 found of NK cells?
An Fc receptor for IgG, confers the ability for NK cells to lyse IgG-coated target cells, known as antibody-dependent cell-mediated cytotoxicity (ADCC)
How are NK cells able to recognize and kill infected cells?
- Contain an activating receptor NKG2D which recognizes surface molecules induced by various kinds of stress, such as infection and DNA damage
- Contain an inhibitory receptor, which recognizes MHC class I molecules, that are expressed by all healthy cells
- When cell is infected, expression of ligands for the activating receptor will be enhanced, while expression of MHC class I molecules are reduced, balance is tilted towards activation/killing by NK cell.
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What cytokine do NK cells secrete; function?
IFN-gamma
Activates macrophages to destroy ingested microbes, thus NK cells provide early defense against intracellular microbial infections
Which cytokines regulate NK cells?
How does each have an effect?
- IL-2 and IL-15 stimulate proliferation of NK cells
- IL-12 activates killing and secretion of IFN-gamma by NK cells; IFN-gamma then activates Macrophages (classical) to destroy
MHC molecules are called what?
Encoded where?
- Human leukocyte antigens (HLA)
- Chromosome 6
MHC class I molecules are expressed on what cells?
The α/heavy chain is encoded by what 3 genes?
Display what antigens?
- All nucleated cells and platelets
- HLA-A, HLA-B, HLA-C
- Peptides derived from proteins, such as viral and tumor Ags located in the cytoplasm (intracellular)
Function of α1, α2, and α3 extracellular domains of the α/heavy-chain of MHC class I?
- α1 and α2 form a cleft, or groove, where peptides bind
- α3 is nonpolymorphic and has binding site for CD8
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MHC class II molecules mainly expressed on what cells?
Encoded in which region and subregions?
Display what Ags?
- Macrophages, B cells, and DCs = ALL APCs
- Encoded by HLA-D region, which has 3 subregions: HLA-DP, HLA-DQ, and HLA-DR
- Display Ags that are internalized into vesicles and typically derived from extracellular microbes and soluble proteins
What makes up the peptide binding cleft of the MHC class II molecule?
What portion of MHC class II has binding site for CD4?
- α1 and β1 domains interact and form cleft = binding groove
- β2 domain has binding site for CD4
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Peptide-loaded MHC class I molecules associate with _______ to form a stable trimer that is transported to the cell surface?
β2-microglobulin
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How are HLA genes inherited?
Why are there virtually innumerable combos of HLA molecules?
- One set of HLA genes from each parent
- Polymorphisms cause each individual to express an MHC profile on his or her cell surface that is different from the halotypes of most other individuals
What role do MHC molecules play in regulating T cell-mediated immune responses?
- Determines if an immune response against a specific Ag will occur protein, since you must inherit the genes for those MHC molcules that can bind the specific Ag and present it to T cells (i.e., ragweed pollen)
- Ensure the correct immune response is mounted against different microbes, i.e., CTL-mediated killing of cells and helper T cell-mediated Ab and macrophage activation for extracellular microbes
Which cytokines stimulate hematopoiesis?
GM-CSF and IL-7
Patients w/ Rheumatoid arthritis respond dramatically to which type of treatment?
TNF antagonists
What is an example of therapeutically administering cytokines to boost reactions?
To mobilize and recruit stem cells from bone marrow to peripheral blood; the cells are then collected from the blood for stem cell transplantation
The spleen serves the same role in immune responses to ______ antigen as LN do in response to _______?
The spleen serves the same role in immune responses to blood borne antigen as LN do in response to lymph-borne antigens
How are antigens trapped in the spleen?
DCs and macrophages
Where are cutaneous and mucosal lymphoid systems located?
How many lymphocytes found here?
Function of these systems?
- Under the epithelia of the skin, GI, and respiratory tracts
- 1/2 of body’s lymphocytes are in the mucosal tissues
- Respond to Ag’s that enter through breaches in the epithelium