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innate immunity
the rapid and relatively non-specific immune response mediated by germline-encoded receptors that recognize common features of pathogens; does not increase with repeated exposure to a given antigen and is critical during the early phases of the host's response to an infection
adaptive immunity
the immune response mediated by antigen-specific lymphocytes reacting to a specific antigen recognized by receptors that are unique to each lymphocyte; increases with repeated exposure to a given antigen due to the development of memory; activation is dependent upon appropriate activation of innate immunity; precursor frequencies of rare responding B and T cells (in a primary response) require time to expand these populations to numbers capable of responding to equivalent numbers of pathogens
adjuvant
basically purified PAMPs; any substance that enhances the immune response to antigens with which it is mixed (i.e., dead bacteria); often included along with specific antigens in vaccines; immunologist's "dirty little secret"; stimulates TLRs/other innate immune sensors (PRRs); innate immunity needs to activate an adaptive immune response so all that "dirty" stuff includes PAMPs that initiate immune signaling when they are recognized by PRRs
antigen
any molecule that can bind specifically to an antibody or a peptide fragment that can be recognized by a T cell receptor
T cell
a subset of lymphocytes defined by their development in the thymus
effector T cells
carry out a variety of functions in an immune response by interacting with other cells in an antigen specific manner; some activate macrophages, some help B cells produce antibody, and some kill cells infected with viruses and other intracellular pathogens
T cell receptor (TCR)
a cell surface receptor for antigen; can only recognize peptide antigens in the context of MHC; each cell only expresses one type which is generated by gene rearrangement during development
B cell
adaptive immunity; one of the two major types of lymphocytes; when activated (by antigens and T cell help) it differentiates into antibody producing cell; recognizes antigens on whole proteins; antigen presenting cell
B cell receptor (BCR)
a cell surface receptor for antigen; can recognize soluble or cell-surface antigens that do not necessarily need to be peptides; each cell only expresses one type which is generated by gene rearrangement during development
antibody
the soluble form of the BCR also known as immunoglobulin; each recognizes one specific antigen (called an epitope) but they all have the same overal structure; produced by plasma cells (activated by B cells) in response to immunization or infection and bind to and neutralize pathogens or prepare them for uptake and destruction by phagocytes
phagocytes
white blood cells specialized to phagocytose extracellular materials including bacteria and dead cells ; macrophages, dendritic cells, and neutrophils
phagocytosis
the internalization of particulate matter by cells; usually phagocytes are macrophages or neutrophils and the particles are bacteria or virus particles; the ingested material is contained in a vesicle (called a phagosome) which then fuses with lysosomes where lysosomal enzymes and other molecules destroy and degrade the pathogen
dendritic cell (DC)
a type of bone marrow derived phagocyte that is a particularly effective antigen-presenting cell; takes up antigen in the peripheral tissues, is activated by contact with pathogens, and travels to the peripheral (secondary) lymphoid organs where it is the most potent stimulator of T cell responses (MHC I/II); takes up and presents antigen in plasma; produces large amounts of antiviral interferons; bridge between innate and adaptive immunity
antigen presenting cell
highly specialized cells that can process protein antigens and display their peptides on the cell surface along with co-stimulatory molecules required for activating naive T cells; include dendritic cells, macrophages, and B cells
co-stimulation
additional signals required for the activation and proliferation of naive lymphocytes when they first encounter antigen (in addition to the signals generated by the binding of antigen to the antigen receptors); such signals are usually delivered to T cells by proteins on the surface of the antigen presenting cell; B cells can receive them from pathogen components such as LPS, from complement fragments, or via CD40 ligand on the surface of an activated antigen-specific helper T cell; receptors include CD30 and CD40 on B cells and CD27 and CD28 on T cells
cross-presentation
the process by which extracellular proteins taken up by dendritic cells can give rise to peptides presented by MHC class I molecules; enables antigens from extracellular sources to be presented by MHC class I molecules and activate CD8 T cells
naive T cell
a T cell that has not been activated
macrophage
another type of bone marrow derived phagocyte that can act as an APC (not as effective as DC); also important as an effector phagocytic cell (engulf bacteria), scavenger cell (clear dead cell debris), and is a key source of pro-inflammatory cytokines in innate immunity (myeloid origin)
granulocytes
a class of white blood cells that includes neutrophils, eosinophils, and basophils
neutrophil
phagocytic cell that enters infected tissues and engulfs and kills extracellular pathogens; white blood cell in peripheral blood (most numerous); also has cytotoxic granules with enzymes; myeloid origin
eosinophil
a type of granulocyte that is important in defense against parasitic infections; also important as effector cells in allergic reactions
basophil
type of white blood cell containing granules that stain with basic dyes; thought to function similarly to mast cells (though they circulate in the blood rather than being tissue resident)
mast cell
a large granule-rich cell found in connective tissues throughout the body; granules store bioactive molecules (including histamine) which are released upon activation; thought to be involved in defenses against parasites and thought to have a crucial role in orchestrating allegic reactions
natural killer cell (NK cell)
non-T, non-B lymphocytes that kill virally infected cells and some tumor cells; bear many invariant inhibitory and activating receptors but unlike T and B cells do not bear unique receptors that are the result of gene rearrangements; important in innate immunity for viruses and other intracellular pathogens and in antibody-dependent cell-mediated cytotoxicity (release of cytotoxic granules); lymphoid origin; recognize and kill tumor/transformed cells with germline encoded receptors
cytokine
small, soluble protein released by cells in certain circumstances that affect the behavior of other cells; have many varying functions and act via specific receptors on the cells that they affect; protein made by a cell that affects the behavior of other cells (particularly immune cells); often called interleukins when made by lymphocytes
chemokine
small chemoattractant protein that stimulates the migration and activation of cells; infected cells can secrete them to attract phagocytic cells and lymphocytes
primary lymphoid organs
the organs where the immune system primarily develops; included the bone marrow and thymus; B cells develop in the bone marrow whereas T cells develop in the thymus from bone marrow progenitors
seconday lymphoid organs
the organs where immune responses are primarily induced; mature naive lymphocytes hang out and wait here to get activated by antigens of APCs; includes the lymph nodes, spleen, and mucosal-associated lymphoid tissue; lymph nodes collect antigens from tissues while the spleen collects antigens from the bloodstream
common lymphoid progenitors
stem cells that give rise to all lymphocytes
common myeloid progenitors
precursor of the macrophages, granulocytes, mast cells, and dendritic cells of the innate immune system (and also of megakaryocytes and red blood cells)
MHC class I
polymorphic cell-surface proteins expressed on all nucleated cells of the body (with few exceptions); present antigenic peptides generated in the cytosol to cytotoxic T cells and interact with the co-receptor CD8
MHC class II
polymorphic cell-surface proteins expressed on only a few specialized types of cells primarily APCs (B cells, macrophages, DCs); present antigenic peptides derived from internalized extracellular pathogens to helper T cells and interact with the co-rector CD4
cytotoxic T cell
also known as a killer T cell and CD8 T cell; expresses the CD8 co-receptor and is activated by peptides in MHC class I molecules; can kill cells expressing the antigen that activates TCR and are important for the clearance of intracellular pathogens and that live and reproduce in the host's cytosol (notably viruses)
helper T cell
also known as CD4 T cell; express the CD5 co-receptor and activated by peptides in MHC class II molecules; play critical roles in the activation of B cells, macrophages, and CD8 T cells
toll-like receptor (TLR)
germline-encoded, non-variable receptors expressed at the surface of macrophages and DCs that recognize pathogen-associated molecular patterns (PAMPs) and are important for innate immune responses; recognition of a PAMP (molecules that are not present in the host) stimulates cells to produce cytokines that help initiate immune responses; recognition can also activate the receptor-bearing cell to initiate adaptive immune responses (ex. signaling induces APCs to express more co-stimulatory receptors like B7 at the surface); humans have 10 and mice have 12
pathogen-associated molecular patterns (PAMPs)
molecules that are hallmarks of certain groups of pathogens that are recognized by non-variable germ-line encoded pattern recognition receptors (PRRs, such as TLRs) on the surface of innate immune cells
CpG DNA
stretches of CpG-rich sequence commonly found in the genomes of DNA viruses (rare in vertebrate genomes, where it is usually marked by methylation); recognized by TLR9 when unmethylated
commensal bacteria
bacteria that form symbiotic relationships with the host (aiding in digestion, preventing harmful bacteria from colonizing, etc)
gram-positive bacteria
stain purple with crystal violet dye due to thick peptidoglycan layer which contains lipoteichoic acid (LTA); LTA is a PAMP recognized by TLR2
gram-negative bacteria
do not stain or retain crystal violet dye; cell wall has thin layer of peptidoglycan and outer layer of lipopolysaccharide (LPS, aka endotoxin) which is a PAMP and recognized by TLR4; LPS is composed of an outer O antigen, core polysaccharide, and Lipid A (this is the component recognized by TLR4)
B7
a co-stimulatory molecule that is expressed at the surface of activated antigen presenting cells and interacts with CD28 on T cells; interaction of CD28 and B7 is necessary as a second signal in addition to engagement of the TCR with its antigen for the activation of T cells
CD28
an activating receptor on T cells that binds to the co-stimulatory molecule B7 expressed at the surface of activated APCs; under most circumstances it must be engaged by B7 in order for a T cell to become activated
Fc region
named Fragment Crystallizable region (referring to how it was discovered); the constant region of an antibody molecule
Fc receptor
cell surface receptors that bind to the Fc region of antibody molecules; typically found on the surface of phagocytes so that opsonized pathogens can be ingested
opsonization
the process by which antibody molecules coat the surface of a pathogen; phagocytic cells (ex. macrophages and neutrophils) can recognize the opsonized pathogen via Fc receptors on their cell surface and ingest the pathogen
humoral immunity
immunity mediated by soluble proteins circulation in the blood such as antibodies and complement
inflammation
characterized by heat, pain, redness, and swelling; four main symptoms are a result of the accumulation of fluids, plasma proteins, and cells of the immune system at the site of injury or infection
complement
a set of plasma proteins that act together to attack extracellular forms of pathogens; coating of pathogens facilitates the removal of the pathogen by phagocytes or kills the pathogen directly
cell-mediated immunity
mediated largely by antigen-specific T cells; requires contact of the antigen specific TCR with the antigenic peptide-MHC complex it recognizes for the T cell to exert its effector role
kinase
an enzyme that catalyzes the addition of a phosphate group to another protein or small molecule; two main classes: serine/threonine and tyrosine
phosphatase
an enzyme that catalyzes the removal of a phosphate group from a protein or small molecule substrate
SH2 domain
protein domain present in many proteins that are part of the immune system signal transduction pathways; recognizes phosphorylated tyrosine residues
transcription factor
a sequence-specific DNA-binding protein that regulates the transcription of target genes via recruitment of coactivators, corepressors, histone modifiers, chromatin remodelers, basal transcriptional machinery, etc
apoptosis
a form of programmed cell death that is common in the immune system; non-inflammatory in nature
pyroptosis
a form of programmed cell death that is activated in response to microbial signals via the inflammasome; inherently inflammatory as it results from cytokines and cytosolic components
polyclonal
a collection of antibodies that consists of a mixture of antibodies with different specificities (i.e., they can bind different epitopes); antibodies are all produced from different B cells with different BCRs; important in an immune response because it increases the potential antigen repertoire and allows for the formation of large antibody-antigen complexes which are more easily cleared by the immune system
monoclonal
collection of antibodies that consists of a mixture of just one type of antibody (i.e., all the antibodies can only bind one specific epitope); all produced from the same clone of B cells; often used because they are easy to produce and having one single antibody versus a pool of polyclonal antibodies reduces the potential for unwanted cross-reactivity in your assay of choice
affinity
the strength of binding of one molecule to another at a single site, such as the binding of a monovalent Fab fragment of antibody to a monovalent antigen
avidity
the total sum of the strength of binding of two molecules or cell to one another at multiple sites
complementarity-determing regions (CDRs)
parts of the V domains of antibodies and T-cell receptors that determine their antigen specificity and make contact with the specific ligand; the most variable parts of the antigen receptor and contribute to the diversity of these proteins; there are three such regions in each V domain
epitope
the exact site on an antigen that is bound to by an antibody/BCR or TCR; one antigen can have many epitopes that different antibody/BCR or TCRs can recognize
isotype
the type that an antibody has based on its constant region (Fc); different effector functions and determine the functional properties of the antibody (ex. IgM antibodies are very good at activating complement, IgE antibodies are not); has no effect on the epitope that the antibody binds since it is determined by the constant region and not the variable region
primary antibody
antibody used in assays that take advantage of antigen-antibody interactions (flow cytometry, western blot, ELISA) that directly recognizes antigen but is not (necessarily) conjugated to an enzyme or fluorophore; it can be monoclonal or polyclonal (but monoclonal will usually provide greater specificity and reproducibility)
secondary antibody
antibody that recognizes the primary antibody as its target antigen; conjugated to an enzyme of fluorophore that will provide the readout for the assay
Fab fragment
fragment of an antibody consisting of a single antigen-binding arm without the Fc region; can bind to epitopes; consist of entire light chain (constant and variable regions) and some of the heavy chain (some of the heavy chain constant region and all of the variable region)
Fc fragment
the fragment of an antibody consisting of the heavy chain constant region stem without either of the antigen binding arms; contain no variable regions
immunogenic
any molecule that, on its own, is able to elicit an adaptive immune response on injection into a person or animal
hypervariable regions
three distinct regions of the antigen-binding site that are extremely variable in sequence; separated in sequence but are adjacent in the structure of an antibody (due to the way the protein is folded); these regions make up the antigen binding site of the antibody and determine its specificity
hapten
a small molecule that can be an antigen but cannot induce an immune response alone; must be conjugated to proteins in order to induce an antibody response
carrier
a protein that a hapten is conjugated to in order to allow the hapten to induce an immune response
NFkB
a transcription factor activated by the stimulation of toll-like receptors and by TCR/BCR signaling; induces many genes important for immune responses
IkB
inhibitor of NFkB; binds NFkB keeping it in the cytoplasm where it cannot act as a transcription factor; when a cell is stimulated by TLR, TCR, or BCR signaling it is degraded which allows NFkB to enter the nucleus and act as a transcription factor
MyD88
an adapter protein necessary for signaling through all the TLRs (except for TLR3)
interferons (IFNa and B)
cytokines that are induced in all cells in response to viral infection; inhibit viral replication and increase MHC class I expression and antigen presentation in all cells; also activate DCs and macrophages and activate NK cells to kill virus-infected cells
effector mechanisms
processes by which pathogens are destroyed and cleared from the body; most of the same are used by innate and adaptive immune responses to eliminate pathogens
septic shock
systemic shock reaction that can follow infection of the bloodstream with endotoxin-producing Gram-negative bacteria; caused by the systemic release of TNFa and other cytokines; also called endotoxic shock
TRIF (TIR domain-containing adaptor-inducing IFN-B)
similar to MyD88; adapter protein for TLR signaling; choice of adaptors in TLR signaling influences which signals will be activated by the TLR; recruitment of this one results in activation of transcription factors IRF3 and IRF7 that leads to production of IFN
IRF3/IRF7 (interferon regulator factor)
transcription factors downstream of the MDA5-MAVS viral RNA sensing pathway; induce the transcription of a number of genes, principally those encoding IFN-a and IFN-B (aka the type I interferons)
RIG-I
the prototypic intracellular helicase that recognizes viral RNAs, initiating a signaling pathway that leads to cytokine production; preferentially recognizes short dsRNA from viruses; contains a CARD domain which mediates interaction with adaptor protein MAVS; also has a regulatory domain (RD) which binds to the dsRNA itself; upon activation, its downstream outcome is upregulation of cytokines via action of NFkB
MDA5
another example of a cytoplasmic sensor for RNA viruses; similar to RIG-I, it is a type of helicase containing a CARD domain (mediating interaction with MAVS) and a regulatory domain (RD); in contrast to RIG-I, it preferentially recognizes long dsRNAs and its downstream outcome upon recognition of viral mRNA is production of Type I interferons
MAVS
an adaptor protein downstream of both RIG-I and MDA5 cytoplasmic sensors of viral RNA; responsible for inducing production of inflammatory cytokines via NFkB activation (downstream of RIG-I activation) and for inducing type I interferon production via IRFs (downstream of MDA5 activation)
V(D)J recombination
the process that recombines different gene segments into sequences encoding complete protein chains of immunoglobulins and T cell receptors; exclusive to developing lymphocytes in vertebrates
V gene segments
gene segments in immunoglobulin and T-cell receptor loci that encode the first 95 amino acids or so of the protein chain; there are multiple different segments in the germline genome; to produce a complete exon, one segment must be rearranged to join up with a J or a rearranged DJ segment
D gene segment
diversity gene segments; short DNA sequences that form a joint between the V and J gene segments in rearranged immunoglobulin heavy-chain genes and in T-cell receptor beta and delta chain genes
J gene segment
joining gene segments; short DNA sequences that encode the J regions of immunoglobulin and T-cell receptor variable domains; in a rearranged light-chain locus, TCRa locus, or TCRy locus, it is joined to a V segment; in a rearranged heavy-chain locus, TCRB lobus, or TCRd locus, it is joined to a D segment
class switch recombination
a somatic recombination process that occurs in activated B cells in which one heavy-chain constant region gene is replaced with another of a different isotype resulting in a switch from the production of antibodies of class IgM to the production of IgG, IgA, or IgE classes; affects the effector functions of the antibodies produced but not their antigen specificity
recombination signal sequence (RSS)
short stretches of DNA flanking the gene segments that are rearranged to generate a V-region exon in antigen-receptor gene loci and which are recognized by the RAG-1:RAG-2 recombinase; they consist of a conserved heptamer and nonamer separated by 12 or 23 base pairs
12/23 rule
the rule that gene segments of immunoglobulin or T-cell receptors can be joined only if one has a RSS with a 12-base-pair spacer and the other has a 23-base-pair spacer; 12-base-pair spacers are also known as "one-turn" due to one physical turn of the DNA, a 23-base-pair spacer is also known as "two-turn" due to two physical turns of the DNA; enzymes (RAG-1, RAG-2) recognizing the shape and sequence of these DNA spacers enforce the 12/23 rule
RAG-1/RAG-2
recombinase proteins encoded by recombination-activating genes which are essential for immunoglobulin and T-cell receptor gene rearrangement; form a complex with other proteins that initiates V(D)J recombination by initially recognizing RSS (following the 12/23 rule) and align them to be targeted for cleavage
Ku70/80
DNA repair proteins required for immunoglobulin and T-cell receptor gene rearrangement; specifically, they bind DNA ends of coding joints previously exposed by cleaveage of RSS
DNA-PK (DNA-dependent protein kinase)
central component of a protein kinase catalytic subunit that works with Artemis to open DNA hairpins and generate palindromic P-nucleotides
Artemis
an endonuclease involved in the gene rearrangements that generate functional imunoglobulin and T-cell receptor genes; specifcally, it opens up the DNA hairpin (formed by Ku70:Ku80 complex following RSS cleavage) for TdT to process DNA ends
DNA ligase IV/XRCC4
pair of enzymes that join together the ends of double-stranded DNA broken during the gene rearrangements that generate functional genes for immunoglobulins or T-cell receptors
P-region diversity (P-nucleotides)
nucleotides found in junctions between gene segments of the rearranged V-region genes of antigen receptors; they are an inverse repeat of the sequence at the end of the adjacent gene segment being generated from a hairpin intermediate during recombination; a significant contributor to immunoglobulin diversity
N-region diversity
resulting from non-templated nucleotides being inserted by the enzyme terminal deoxynucleotidyl transferase (TdT) into the junctions between gene segments of T-cell receptor and immunoblobulin heavy-chain V regions during gene segment joining; stretches of nucleotides are translated and thus markedly increase the diversity of these receptor chains
TdT (terminal deoxynucleotidyl transferase)
enzyme that inserts nontemplated N-nucleotides into the junctions between gene segments in T-cell receptor and immunoglobulin V-region genes during their assembly
somatic hypermutation
extensive mutation that occurs in the V-region DNA sequence of rearranged immunoglobulin genes in activated B cells resulting in the production of variant immunoglobulins, some of which bind antigen with a higher affinity; those resulting in higher affinity are selected for and propagate in the repertoire; affect only somatic cells and are not inherited through germline transmission
AID (activation-induced cytidine deaminase)
enzyme that contributes to somatic hypermutation of immunoglobulin gene variable regions by deaminating DNA directly at cytosine; depending on how this DNA lesion is repaired it can lead to a permanent base change at the deaminated site; also involved in isotype switching and gene conversion
transgenesis
the introduction of cloned DNA into the germline of an animal such as a mouse; the transgene is randomly inserted into the host chromosome; the position of insertion and copy numbers differ host to host; invariably the transgene typically leads to overexpression of the gene it encodes due to the increase in copy number; an example is the expression of diptheria toxin receptor (DTR) fused to green fluorescent protein (GFP) driven under a cell-specific promoter (ex. CD11c promoter in dendritic cells) in a mouse, thus the DCs in the mouse (and only the DCs due to the promoter) express both the DTR and GFP, with addition of diptheria toxin (DT) these DCs are ablated from the mouse (and all other cell types survive)
combinatorial diversity
the diversity among antigen receptors generated by combining separate units of genetic information, comprising two types; 1) receptor gene segments are joined in many different combinations to generate diverse receptor chains; 2) two different receptor chains (heavy and light in immunoglobulins, alpha and beta/gamma and delta in T cell receptors) are combined to make the antigen-recognition site
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