Cells and Signals of the Immune System/Major Histocompatibility Complex/Innate Immunity

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The two types of immunity are innate and adaptive immunity. What cells mediate innate immunity?r	Monocytes/macrophages, neutrophils, natural killer (NK) cells, gamma-delta T cells.
Adaptive immunity is composed of two responses. What cells mediate each response?	Humoral immunity is mediated by B lymphocytes. Cell-mediated immunity is mediated by T lymphocytes (also macrophages, NK cells)
B and T cell proliferation in early lymphocyte maturation is stimulated by which cytokine?	Interleukin 7
What interacts with the T cell receptor (TCR) of an immature, double-positive T cell (CD4+/CD8+) to signal differentiation into a single-positive cell? In what organ does this occur?	Interaction with either major histocompatibility complex (MHC 1) (CD8+) or MHC 2 (CD4+) in the cortex of the thymus.
What two processes eliminate immature T cells lacking proper antigen receptor specificities?	Positive selection selects for lymphocytes with TCRs that recognize self-MHC proteins, ensuring that only T cells that recognize MHC mature. Negative selection eliminates autoreactive T cells that bind to MHC with hgih affinity.
What mechanism drives cell elimination in positive selection?	T cell that cannot bind to self-MHC molecules undergo apoptosis.
Apoptosis of T-helper cells (CD4+, Th) or cytotoxic T cells (CD8+, Tc) bearing TCRs for self-proteins is the result of what process?	Tolerance, which prevents autoimmune reactions.
What cytokine released by activated Th further stimulates Th-cell survival/proliferation?	IL-2. It binds to the IL-2 receptor on Th cells causing further proliferation.
Name the two signals that are needed to activate T cells.	Th first signal is the MHC/antigen complex interaction with a TCR specific for that antigen. The second is the costimulatory signal of the CD28 protein on the t cell with the B7 protein on the antigen-presenting cells. (APCs)
What is the result of an interaction between a T cell and an APC in the absence of costimulation?	Anergy and unresponsiveness of T cells.
What T cell protein displaces CD28 from B7, inhibiting T cell activation and ensuring T cell homeostasis?	Cytotoxic T-lymohocyte antigen 4 (CTLA-4)
What is a consequence to t cells that lack CTLA-4?	It is thought that cells without CTLA-4 participate more often in autoimmune processes.
Which MHC class molecule presents processed antigens from organisms that have been phagocytosed? What cells possess this MHC class?	MHC-2 complexes on professional APC present extracellular, phagocytosed proteins to Th cells.
What cells function as professional APCs?	Dendritic cells, macrophages and B cells.
What is the source of antigen presented by MHC-1 molecules? What cells possess this class?	MHC-1 complexes on all nucleated cells present intracellular proteins to Tc cells.
What is the cluster of polypeptides present in all T cells that is important in signal transduction by the TCR?	The CD3 complex.
Induction of which of the T-cell helper lines (Th1 or Th2 elicits a more effective response against intracellular pathogens such as Mycobacterium tuberculosis?	Th1 cells are more effective against intracellular pathogens.
Which cytokine released by Th1 cells is involved in macrophage activation?	y-interferon (y-INF)
What other signaling pathway results in macrophage activation?	The interaction of CD40 on macrophages with CD40L on T cells.
What transcription factor is involved in both y-interferon and CD40/CD40L signaling?	Nuclear factor kB
How do macrophages respond to y-interferon and CD40/CD40L signaling?	Cytokine release, increased microbial activity, increased phagocytic activity (through upregulation of B7 and MHC2)
Once activated, what are the major cytokines released by macrophages?	Tumor necrosis factor (TNF), IL-1 and iL-8 (leukocyte recruitment), IL-6 (lymphocyte activation) and il-12 (Th1 differentiation)
What are the microbidal substances produced by activated macrophages?	Reactive oxygen species, nitric oxide and lysosomal enzymes.
What are the main effector cells and cytokines of delayed hypersensitivity?	Macrophages induce differentiation of naive Th cells into Th1 cells by secretion of IL-12. IL-12 acts on NK cells to produce y-IFN which also promotes Th1 differentiation. Th1 cells in turn release y-interferon, activating macrophages.
Against what pathogens is delayed hypersensitivity needed?	Intracellular pathogens (M tuberculosis, Salmonella typhimurium and Histoplasma)
Patients with T cell deficiencies are most susceptible to what families of pathogens?	All severe T-cell deficiencies have patients particularly susceptible to mycobacterial, viral and fungal infections.
How is the of a T cell by a superantigen different from that by a typical antigen?	Superantigens (staphyloccocal toxic shock syndrome toxin (TSST) bind to MHC2 protein directly and complex with the Vb chain of the TCR on Th cells. They are not processed by the APCs.
What is the result of superantigen activation of Th cells?	Massive Th cell activation and cytokine release, resulting in shock
Which cytokine induces naive Th cells into mature Th2 cells?	IL-4
What cytokines do Th2 cells produce? What properties do these cytokines share?	IL-4, IL-5, IL-10, and IL-13. All are anti-inflammatory and antagonize Th1 cells.
What cytokines aid B cells in antibody production?	IL-4 and IL-5
What functions do IL-4 and IL-5 from Th2 cells serve in helminth immunity?	IL-4 induces helminth-specific immunoglobulin E (IgE) antibodies and IL-5 activates eosinophils.
What cytokine is implicated as a mediator of asthma (airway hyperresponsiveness)?	IL-13
By what two main methods do CD8+ cells kill virus-infected, graft and tumor cells?	Cytotoxic T cells can lyse infected cells or induce apoptosis.
MHC-1 molecules on allogenic donor cells have what role in graft rejections?	They are recognized by Tc cells which can kill grafted cells.
Which mature immune cell has receptors for whole, unprocessed antigens and does not require MHC presentation?	B cells, which actually present antigens themselves via MHC-2 to CD4+ helper cells in the process of activation, can recognize soluble or cell-associated antigens.
Which type of antigens can induce antibody production by B cells without the aid of helper T cells (ie T cell independent response)?	Multivalent antigens (bacterial capsule polysaccharides, DNA, RNA and lipids) bind many IgM (immunoglobulin M) molecules and cross-link IgM receptors on B cells
Where does B-cell differentiation occur?	B cells undergo differentiation in the bone marrow.
What is the predominant antibody released in the initial stages of the primary humoral response?	IgM. Following a lag phase either IgG,IgA or IgE appear in the secondary response
What is class switching of antibodies?	The process that changes IgM to IgG, IgA or IgE.
What cells and signals are involved in class switching?	Th-cell CD40 ligand interacts with B-cell CD40, inducing the release of IL-4, IL-5, and y-INF, which signals class switching.
X-linked hyper IgM syndrome is an inherited disorder where the CD40 ligand on the T cells is defective. How would this affect B cells?	Inability to perform isotype switching, resulting in hypersecretion of IgM.
How would the same syndrome affect macrophages?	The CD-40-CD40L interaction is necessary for macrophage activation by T cells. Macrophages cannot be activated, resulting in susceptibility to intracellular microbes.
What are the main steps in B-cell presentation of antigens to helper T cells?	Antigen-specific B cells bind to native antigen with membrane-bound immunoglobulin molecules. After internalization and processing of the antigen in the endosome, epitopes are presented on the B-cell surface via an MHC-2 molecule where it is then presented to T cell,
One of the causes of severe combined immunodeficiency (SCID) is a lack of functional IL-7 receptors. What cells are depleted? How is immunity affected?	Since T-cells require IL-7 for development, both cell-mediated and humoral responses would be diminished.
What would be different about the T cells in a patient with DiGeorge syndrome compared to that of a person without it (DiGeorge syndrome results in thymic hypoplasia)?	T cells differentiate in the thymus; abnormal thymic structure would result in a lack of T cells.
What immune cell kills infected cells lacking MHC-1 proteins?	NK cells destroy infected cells that lose the ability to synthesize MHC-1 proteins.
NK cells are activated by which cytokines?	IL-12 and y-interferon.
Which cytokines are responsible for the increased production of C-reactive protein during an acute-phase response in innate immunity?	IL-1, TNFa and IL-6 induce the liver to produce C-reactive protein.
What cytokine is chemotactic for neutrophils?	IL-8 along with a complement component (C5a)
Which cytokine has a similar function to granulocyte-macrophage colony-stimulating factor (GM-CSF)?	IL-3 is made by activated Th cells and supports the growth and differentiation of bone marrow stem cells.
What is the major histocompability complex (MHC) also known as human leukocyte antigen (HLA) complex?	Sets of higher polymorphic genes, whose final protein products regulate the immune response, especially antigen (Ag) presentation to T cells.
What chromosome contains the MHC in humans?	Short arm of chromosome 6
What are the two classes of MHC? What sets of HLA genes are associated with each class? what do these individual HLA genes actually encode for?	Class 1-HLA-A, HLA-B, HLA-C 2. Class 2-HLA-DP, HLA-DQ, HLA-DR. The individual HLA genes encode for the a-chain of the MHC class 1 molecule, and the a and B chains of the MHC class 2 molecule.
How are MHC inherited and expressed?	Each person has two haplotypes (two sets of MHC) with one parental set and one maternal set expressed in a codominant gene fashion (both paternal and maternal genes are expressed)
How many MHC molecules can an individual make?	Class 1- 2 MHC haplotypes x 3HLA types=6 Class 2- 2 MHC haplotypes x 4 HLA types (DR has two B chains, either of which can pair with the a chain) = 8
Name the HLA haplotypes associated with each of the following diseases	Multiple sclerosis: HLA-DR2 Type 1 insulin dependent diabetes mellitus- HLA-DR3/DR4 Rheumatoid arthritis- HLA-DR4 Hashimoto disease- DR3/DR5 Hemochromatosis- HLA-A3 Graves disease- HLA-B8, HLA-DR3 Seronegative spondyloarthropathies (Eg ankylosing spondylitis, Reiter syndrome)- HLA-B27
What is the importance of MHC classes 1 and 2 proteins?	Enable T cells to recognize foreign antigens.
What is the structure of MHC class 1	Structure= 1 x (a heavy chain) + 1 x (B2 microglobin)
Describe the a heavy chain's structure. Where is the peptide binding groove?	Three extracellular domains (A1 and a2 form the peptide binding groove) and a3 anchors the protein to the surface of the cell by a single transmembrane domain.
What are MHC class 1 proteins and where are they found?	Membrane glycoproteins on the surface of most nucleated cells and platelets.
What cells lack MHC class 1 proteins?	Red blood cells, (RBCs), neurons and some tumor cells.
What is the function of MHC class 1 proteins?	They bind peptides derived from intracellular proteins (both self and foreign) and present them to cytotoxic T lymphocytes (CTLs)
MHC-TCR	The MHC-TCR interaction is a complex interplay involving not only the identification of different portions of antigen by both receptors, but also receptor interaction with each other. The APC or somatic cell presents the antigen via MHC-2 or MHC-1, respectively. The T cell's TCR then interacts with the antigen via distinct antigen residues as well as contact residues on the MHC molecule. (Note that the BCR, MHC receptor and TCR all recognize different residues of the pathogen).
How do proteins become associated with MHC class 1 molecules?	Proteins in cytosol are routinely degraded to peptides and transported via a peptide transporter (TAP complex) into the endoplasmic reticulum, where they bind to newly synthesized HLA class 1 proteins.
What are sources of foreign proteins associated with MHC class 1 molecules? What happens to cells presenting foreign antigens?	Viruses, intracellular bacteria and parasites, or neoantigens (ie the cell is a tumor cell). These cells are lysed by CTLs
What is the structure of MHC class 2 molecules?	Structure = 1 x (a chain) + 1 x (B chain)
Describe the structure of the a and b chains. Where is the peptide binding groove located?	Each has two extracellular domains (a1 and B1) and one transmembrane domain (A2 and B2). peptide binding groove is formed by the a1 and b1 extracellular domains of each chain.
Where are MHC class 2 molecules expressed?	Antigen-presenting cells-monocytes/macrophages, dendritic cells, B lymphocytes Langerhans cells, activated T cells, and activated endothelial cells.
MHC class 2 molecules are cell surface proteins. What is their function?	Bind and present exogenous peptides to CD4+ helper T lymphocytes.
How are MHC class 2 molecules loaded with peptide?	Vesicle containg endocytosed and cleaved extracellular protein fragments fuse with vesicles containing MHC class 2 molecules. In these vesicles, they are loaded onto MHC class 2 and are transported to the surface.
What prevents MHC class 2 molecules from binding peptides before fusion with vesicles containing endocytosed antigen?	The invariant chain blocks the peptide-binding groove of MHC class 2 molecule as it is transported through the cell. the invariant chain is degraded within the vesicle that contains processed antigen for loading.
What are the two main functions of innate immunity?	First line of defense against microbes (eg skin and mucosa) and stimulates the adaptive immune response (Eg phagocytes act as antigen-presenting cells (APCs) to induce the differentiation of T cells and secrete interleukin 12 (IL-12) to induce Th1 differentiation.)
Which system is able to respond to a broader array of foreign motifs, innate or adaptive immunity? Why?	Adaptive immunity. The recombination of antigen receptor genes allows adaptive immunity to recognize 10^7 antigens. Recognition receptors used in innate immunity lack recombination ability.
Which system is better at discriminating self from nonself, innate or adaptive immunity?	Innate immunity. Adaptive immunity is responsible for autoimmunity, whereas there is no known autoimmunity associated with the innate immune system.
How does the innate immune system distinguish between foreign and self?	Innate immunity occurs in response to motifs that are characteristic of microbes but not of mammalian cells (Eg gram-negative lipopolysaccharide LPS), gram positive teichoic acid, and viral double-stranded RNA)
Why have microbes not adapted to avoid the motifs recognized by innate immunity?	Innate immunity targets motifs that are indispensable to the microbe.
Name the three different epithelial layers of the human body that are considered important aspects of innate immunity.	Skin, gastrointestinal (GI) mucosa, and respiratory epithelium. Realize that the alimentary and respiratory tracts are contiguous with the external environment.
Name the principal effector cells of the innate immune system apart from epithelial cells:	Monocytes/macropahges. Neutrophils Natural killer (NK) cells.
What endothelial surface structure allows rolling of leukocytes along the endothelial wall adjacent to infection?	E-selectins weakly bind to carbohydrate ligands on leukocytes, resulting in alternating attachment/detachment (ie rolling along the endothelial surface)
What endothelial surface structure allows for extravasation of leukocytes into the interstitial area of infection?	Vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) bind strongly to integrins on leukocytes allowing for extravasation.
Mannose receptors and scavenger receptors are mechanisms to identify and ingest microbes utilized by what type of phagocyte?	Macrophages.
How do NK cells identify selected cells?	NK cells identify virus-infected cells by failing to identify host major histocompatibility complex 1 (MHC-1). MHC-1 molecules are normally present on the surface of host cells and inhibit NK cell killing, but are down-regulated when infected by viruses and other intracellular pathogens.
How do NK cells kill infected cells?	NK cells (and cytotoxic T cells) use perforins (create pores in the cell membrane) and granzymes (induce apoptosis)
Deficiencies of NK cells predispose to what types of infections?	Intracellular infections, including intracellular microbes and viruses.
Of the three effector cells of innate immunity (macrophages, neutrophils, NK cells), which is least likely to injure host tissue?	NK cells, which only attack those cells lacking a host MHC-1. On the other hand, macrophages and neutrophils can injure host tissue via nonspecific reactive oxygen intermediates.
Which CD marker is useful for distinguishing NK cells from other immune cells? What is the function of this marker?	CD16 binds the Fc region of immunoglobulin G (IgG)
Which of the complement pathways is considered part of the adaptive immune system?	The classical pathway. The alternative pathway is triggered by direct recognition of exterior features of the microbe. The lectin pathway is triggered by mannose-binding lectin, which attaches to microbial surfaces containing the mannose sugar. In contrast, the classical pathway relieas on IgM, IgG1, or IgG3 to recognize and attach to the microbe and thus is dependent on adaptive immunity.
Antibodies/immunoglobulins (Igs) are synthesized by B cells and perform what general functions?	Antibodies facilitate phagocytosis by opsonization and neutralize toxins and viruses.
Define the following :	Isotype: Antibodies that differ by constant regions, ie, IgG, IgA, IgM, IgE, IgD. Idiotype: antibodies that differ by hypervariable region. Allotype: antibodies that differ among individuals due to polymorphisms (more than two alleles) in heavy and light chains.
A simple Y shaped antibody is composed of two heavy chains and two light chains (named according to molecular weight) connected by disulfide bonds. Each chain is composed of variable and constant regions. What are the functions of these regions?	Variable regions of both heavy and light chains mediate antigen binding. The constant regions of the heavy chains serve effector functions binding to receptors on immune cells (eg IgE can attach to mast cell receptors, IgG can attach to natural killer (NK) cells) and activating complement)
What are hypervariable regions?	Three sequences of amino acids with profound variability located within the variable regions of both heavy and light chains. they are responsible for the specificity of antibodies.
How many heavy-chain constant domains (constituents of constant regions) are present on IgG, IgA, IgM and IgE?	IgG and IgA have three while IgM and IgE have four (all light chains have one constant domain)
What are the Fab and Fc fragments? Which one is at the amino terminus and which one is at the carboxyl terminus? What separates Fab and Fc fragments?	Fab fragment is the part of an antibody that contains the antigen-binding sites located at the amino terminus. The Fc fragment, located at the carboxyl terminus, is composed of heavy chain constant domains and serves effector functions. Fab and Fc are separated by the hinge region.
What is the function of the hinge region of the immunoglobulin?	Allows flexibility within an antibody, resulting in a broader array of binding conformations.
What does the identification of the presence of both k and lambda light chains suggest about the sample of antibody?	The antibodies are not monoclonal. Antibodies have either k or lambda chains, but never both. Thus, the presence of both implies that there must be at least two different types of antibodies in the sample.
What is the function of the J chain on IgA and IgM isotypes?	The J chain plays a critical role in the stabilization of the multimeric forms of IgA and IgM. In its absence, all isotypes would be monomeric.
Define the following	Affinity: Binding strength at a single antibody variable region and antigen epitope. Valency: Number of sites at which an antibody binds an antigen. Avidity: Overall strength of an interaction between an antibody and antigen, determined by both affinity and valency.
What isotype has the highest avidity and why?	IgM, because it has 10 binding sites (ie, valence of 10)
What isotypes of antibodies allow for B cells to achieve antigen presentation?	The membrane-bound form of IgM and IgD (which only exists as a membrane-bound form) functions to recognize and allow endocytosis of antigens within the naive B cells , allowing them to subsequently be presented to T cells. This constitutes the recognition phase of humoral immune response.
How does the structure of IgM in its secreted form differ from its membrane bound form? What is the function of secreted IgM?	Membrane bound IgM is a monomer, but secreted IgM a pentamer. IgM is the main antibody in the primary response of humoral immunity.
IgG is the main antibody in the secondary response of humoral immunity, though both IgG and IgM can opsonize. How do they differ in this regard?	IgG can directly opsonize, while IgM acts indirectly through complement activation.
Microbial pathogens entering the nasopharynx will most likely encounter which immunoglobulin isotype?	Dimeric IgA is concentrated in secretions (mucosa, tears, saliva, respiratory/intestinal/genital secretions) to neutralize microbial pathogens.
What protects IgA from being digested by intestinal enzymes?	The secretory component synthesized by epithelial cells protects IgA from proteolysis.
What two immune processes does IgE mediate?	Type 1 hypersensitivity (allergy, anaphylaxis) Helminth immunity.
Antibodies are found associated with the surfaces of which types of cells?	B cells (IgM and IgD, recognition phase, are membrane bound receptors). Antibodies bind to other receptors on the following cells: mononuclear phagocytes (IgG, opsonization), NK cells (IgG, antibody dependent cellular cytotoxicity), mast cells and basophils (IgE, anaphylaxis), and eosinophils (IgE, helminth immunity)
What isotype is most abundant in serum?	IgG
What isotype is produced in the largest amount?	IgA. About two-thirds of all antibody production is IgA, found in secretions over extensive surface area of the body.
Which immunoglobulin isotypes can initiate the classical complement cascade?	IgG an IgM both have Fc regions which are recognized by C1q- the first molecule in the complement cascade.
What is the most common immunoglobulin isotype found in fetal serum?	Maternal IgG
Why is IgG the only maternal isotype found in the fetus?	The Fc portion of the IgG molecule is recognized by a special type of Fc receptor in the placenta, thus facilitating its transfer.
Why is IgA the predominant isotype found in milk?	Again this is due to specific Fc receptor-Fc region mediated transfer of IgA, facilitating secretion of IgA into the breast milk
What is the immunoglobulin isotype primarily produced by the fetus?	IgM, but the fetus also produces very small amounts of IgG and IgA.
Define antibody-mediated cell cytotoxicity (ADCC). What two cells utilize ADCC? What two isotypes are involved in each case?	process by which Fc receptors on a cell bind Fc portion of antigen-bound antibodies, resulting in activation of that cell. NK cells via IgG lyse target cells. Eosinophils via IgE kill helminths.
An overwhelming proportion of a single clone of IgM antibodies in serum is suggestive of what disease?	Waldenstrom macroglobulinemia. Because IgM is the largest immunoglobulin with the most binding sites, patients with advanced disease are likely to exhibit hyperviscosity syndrome, which can lead to irreversible blindness.
An overwhelming proportion of a single clone of IgG or IgA antibodies in serum is suggestive of what disease?	Multiple myeloma. Patients afflicted by this disease often exhibit punched out lytic lesions within the bones, resulting in bone pain and hypercalcemia.
Name the three complement pathways and how they are activated.	The classical complement pathway is activated when C1q binds to antigen-antibody complexes consisting of IgG or IgM, or directly to the surface of certain pathogens or altered host cells. The alternative pathway is activated when small amounts of C3b bind spontaneously to a microbial cell surface and then bind factor B. The lectin pathway is activated by mannose-binding lectin (MBL), which recognizes mannose residues on microbial cell surfaces. MBL then triggers other proteases.
Why do free IgM or IgG not activate the complement cascade?	Binding of IgM/IgG to a microbial surface exposes the complement-binding regions.
How do IgM and IgG differ with respect to binding C1?	Only one IgM molecule is needed, whereas multiple IgG molecules are needed to bind C1q. Thus IgM i s more potent at activating complement.
C3 convertase cleaves C3 to C3a (and C3b) in each complement pathway, but how does C3 convertase differ among pathways?	Classical and lectin pathways: C3 convertase is (C4b2a) Alternative pathway: C3 convertase is (C3bBb)
In the classical and lectin pathways what enzymes cleave C4 to C4b (and C4a) and C2 to C2a and (C2b)?	Classical C1 (subunits C1q binds the Fc fragment, C1r and C1s are proteolytic) Lectin: Proteases triggered by MBL
In the alternative pathway a small amount of C3b is generated. Once C3b binds B (forming C3bB) on a microbial surface, what enzyme cleaves B?	Factor D cleaves b to Bb, converting C3bB to C3bBb (ie, C3 convertase)

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