Chapter 1, Section 1. Basic Science Flashcards
What genes are associated with MHC-II
HLA-DP, HLA-DQ, HLA-DR
How many isotypes of human IgG are there
4 - IgG1, IgG2, IgG3, IgG4
Where does Omalizumab bind
What kind of bond is there between Ig heavy-heavy and heavy-light chains
disulfide bonds
What is Ig affinity
What is Ig avidity
strength of binding between the antibody and the epitope. It is indicated by the Ksubd. A numerically lower Ksubd indicates higher affinity
Avidity is the net effect of affinity and valence. It is an estimate of the overall strength of the binding between Ig and antigen. A low-affinity IgM can produce a high-avidity interaction by simultaneous binding to multiple antigen epitopes through 10 contact sites on each IgM molecule
Titermax adjuvant - what copolymers are in it
Copolymers polyoxypropylene (POP) and polyoxyethylene (POE)
What are the nucleotides (4)
Which are purines? Which are pyrimidines?
adenine (A), guanine (G), thymine (T), cytosine (C)
A,G are purines
T,C are pyrimidines
How does lack of costimulation function in tolerance
lack of costimulation, or lack of an innate immune system response to the antigen, blunts the required upregulation to produce costimulation (a second signal). T lymphocytes will recognize the antigen but receive no support to activate. If this happens repeatedly where the cell is recognized but no costimulation is forthcoming the lymphocyte becomes unresponsive to that antigen (anergic)
Once the TCR-antigen HLA complex is formed, how does activation occur:
activation requires a second signal or costimulation
the most important cytokine is IL-2 and its receptor CD25
proliferation is clonal; it is stimulated by IL-2, clonal expansion preserves the specificity of the T lymphocyte for its particular antigen
What cytokines (2) do Tregs need to survive
IL-2 and TGFbeta
tolerance is maintained in general by IL-10 (turns off innate cells) and TGFbeta (turns off innate and lymphoid cells)
How many constant regions are there in IgG, IgA, and IgD
How many constant regions are there is IgM and IgE
3
4
What is the TCR complex made up of
TCR, CD3, two zeta chains
how are somatic mutations passed down
these occur with cells outside of the reproductive system, so do not get passed to subsequent generations. However, a mutation early enough in the process can affect a lot of the cells and this can cause disease - mosaicism
What type of molecule transports amino acids to ribosome
tRNA
Lck
an SRC family kinase, noncovalently associated with CD4 and CD8
basically turns on (phosphorylates) the zeta and CD3 proteins by way of their ITAMs
Review the MHC class II antigen-processing pathway
What cytokines are associated with MHC class I cells
interferon alpha, interferon beta, and interferon gamma
What part of the TCR imparts the most significant sequence variability
the alpha-beta CDR3 (just like in antibodies)
what type of molecule is copied from DNA and travels to ribosome
mRNA
What genes are associated with MHC-1
HLA-A, HLA-B, HLA-C
IP3
1,4,5 triphosphate
more importantly, the generation of IP3 stimulates an increase in cytosolic calcium from the ER.
For the ADAM33 gene, name the associated protein, the protein function, and relevance in atopy
type 1 transmembrane protein, cell-to-cell interactions, increased risk of asthma and bronchial hyperresponsiveness
What do effector CD4 cells do (3)
induce differentiation of T lymphocyte response to either Th1, Th2, Th17
What is the most variable part of the Ig molecule
CDR3.
VsubL and VsubH form the antigen-binding sites that consist of complementarity-determining regions which account for antibody diversity. There are 3 CDRs in each V region
Where does peripheral tolerance occur
this occurs in the peripheral tissues when a mature lymphocyte encounters a self-antigen
same as before, if the T cell reacts to self it can either 1) undergo apoptosis 2) become anergic or 3) become Treg cells
if a B cell reacts to self in the periphery, it will either become anergic or be deleted through apoptosis
What is the toxin associated with Strep Pyogenes superantigen disease
SPE-C - strep toxic shock syndrome
What state of being is a T cell in when it recognizes an antigen but does not receive costimulatory signals
this is anergy
T/F T cells only recognize antigens that are presented as part of the MHC complex (MHC restriction). This restricts them to ________
T, peptide
Mutations in SAP (what is it?) cause what disease
SAP = SLAM-associated protein
brings SLAM and Fyn together. downstream Fyn binds to CD3
mutations lead to X-linked lymphoproliferative syndrome (XLPS)
Review T-Cell Differentiation
What happens to cells repeatedly presenting self-antigen without innate response
what overall protein system does this involve
They have Fas which interacts with FasL on the T cell and this can delete the self-reactive T cell or cause the death of the activating cell
This involves the caspase system
Review Summary of T and B Cell Tolerance
T/F Alternative splicing changes Ig from transmembrane to secretory form
True
NFkappaB
transcription factor essential for cytokine synthesis and plays an important role in lymphocyte development, neoplasms, and formation of secondary lymphoid organs
What causes ALPS (autoimmune lymphoproliferative syndrome)
mutations in Fas and caspase system in general. The cells accumulate and don’t know when to die.
Key Fact
Mutations in what gene leads to APS (autoimmune polyglandular syndrome)
AIRE gene
lymphocytes fail to have tolerance, they are not deleted or tolerated to endocrine-related self antigens. The endocrine organs are attacked by autoreactive T lymphocytes and autoantibodies
Review “Costimulator Expression and Function”
Define “Immunogen”
molecule that induces an immune response (used interchangeably with “antigen”)
For the 5q22-32 gene, name the associated protein, the protein function, and relevance in atopy
CD14, LPS receptor, both increased/decreased risk of asthma/atopy
Rac-GTP
another molecule activated by another GDP/GTP exchange that activates JNK to phosphorylate Jun, which also turns on AP-1
What is a superantigen
antigens that activate a large number of polyclonal T lymphocytes by binding outside the MHC antigen cleft and cause massive cytokine release
Nucleic Acid Antigens
What immune cells are involved (3)
What surface molecules are involved? (3)
Prototypical vaccines (1)
Immune cells = B cells, CTLs, DC
Surface molecules = MHC Class I, MHC Class II, TLR
Vaccines = DNA vaccines in clinical trials
ZAP-70
deficiency in this leads to what clinical syndrome
Syk family kinase
deficiency leads to a SCID with NO CD8 cells or T-lymphocyte function, but normal B lymphocytes and NK cells.
How does T-lymphocyte central tolerance work
A T-lymphocyte precursor is exposed to a self-antigen in the thymus. First, the T cell has to bind well enough to MHC (positive selection). Secondly it has to not react to self-antigens (negative selection)
If it does react to self, it either undergoes apoptosis or develops into a Treg cell
How does B cell tolerance work
precursor B cells are exposed to self-antigen in the bone marrow during development. If B cells are exposed to self one of three things can happen: 1) apoptosis (negative selection) 2) receptor editing 3) anergy
What is the inheritance pattern of MHC molecules
MHC molecules are co-dominant, which means that a given individual expresses one haplotype from each parent. This means that MHC from both parents is expressed on cell surfaces
What are the two general forms of Ig
membrane bound
secreted
For the 3p21-22 gene, name the associated protein, the protein function, and relevance in atopy
CCR5, chemokine receptor, protection against nonallergic asthma
What do activated T cells become when they grow up
They become effector or memory T cells
What cellular markers do T cells in the thymus carry
double negative (CD4- and CD8-)
CD3+
after proceeding through education in the thymus, the cells become single positive
What is the structure of the Ig molecule
Ig molecule is a polypeptide heterodimer composed of two identical light chains and two identical heavy chains connected by disulfide bonds
NFAT
nuclear factor of activated T lymphocytes (NFAT), antigen-activated transcription factor for expressing genes encoding for cytokines (including IL-2, IL-4, TNF) usually in association with AP-1 (transcription factor)
Review this table on leukocyte Fc receptors
Freund’s adjuvant - what is it
emulsified in bacterial products (BCGs)
What is the CD deficiency that leads to SCID (key fact)
CD3 deficiency
What is the general structure of the alpha-beta TCR
heterodimer of alpha and beta chain, each with two Ig-like domains. Each alpha and beta chain consist of a variable (V) and constant (C) domain, a transmembrane hydrophobic region, and a short cytoplasmic tail with NO SIGNALING ability (requires accessory molecules for signal transduction)
Heavy chains are designated by what letters of the Greek alphabet
gamma (G), alpha (A), mu (M), epsilon (E), delta (D)
Key Fact
In B cell central tolerance, what light chain subunit comes first
the kappa light chains are rearranged first in central b lymphocyte tolerance. If the receptor reacts too much to self then then the process of receptor editing is started with lambda chains
Key fact - what MHC receptor do CD8 cells go for? How about CD4 cells
CD8 - MHC I
CD4 - MHC II
What happens with too-little Ig glycosylation
What happens with too-little Ig galactosylation
What happens with sialic acid enrichment in IVIG
poor function, can’t bind to Fc receptors, can’t activate complement
associated with hyper-inflammatory states
this significantly increases IVIG anti-inflammatory activity
Protein Antigens
What immune cells are involved (3)
What surface molecules are involved? (2)
What is the B-cell response? (3)
Prototypical vaccines (2)
Immune cells = B-2 cells, T cells, “T-cell-dependent”
Surface molecules = MHC Class I, MHC Class II
B-cell response = isotype switch, affinity maturation, induced memory response
Vaccines = Diphtheria, Tetanus
T/F Somatic hypermutation leads to changes in the V but not the C regions
True
What are virus strategies to evade MHC class I presentation?
Give examples . . .
HSV can block TAP transportation
CMV can remove MHC class I from the ER
What cytokines are associated with MHC II
interferon gamma only
How are light chains (on Ig) identified
they are identified by their C regions: kappa is coded on chromosome 2 and lambda is coded on chromosome 22
an Ig molecule has either KK or LL but never 1 of each. Similarly, a B lymphocyte will produce only K chains or L chains, never both
For the 5q31 gene, name the associated protein, the protein function, and relevance in atopy
IL-13, cytokine that induces IgE secretion, mucous production, and collagen synthesis. Increased risk of asthma, bronchial hyperresponsiveness, SPT responsiveness. Linked to response to Singulair
What is “epigenetics”
changes in gene function that occur without a change in the sequence of DNA
often occur due to environmental interactions that cause methylation and histone modification
Lipid Antigens
What immune cells are involved (2)
What surface molecules are involved? (2)
Immune cells = NK cells, gamma delta cells
Surface molecules = MHC-like, CD1(NKT)
For the ADRB2 gene, name the associated protein, the protein function, and relevance in atopy
B2 adrenergic receptor, adrenaline/noradrenaline receptor. Relevance is Arg/Arg phenotype with decreased albuterol response compared with Gly/Gly phenotype at residue 16
What cells have MHC class I
almost all nucleated cells
How can the ratio of K to L bearing lymphocytes help oncologists
the ratio of K-bearing lymphocytes (remember, the kappa chain is rearranged first, the lambda only if receptor editing is needed) to lambda bearing lymphocytes is an indication of clonality
therefore, it is useful to diagnosing and typing B-lymphocyte lymphomas
What is a tolerogen
A tolerogen is an antigen that induces tolerance
A foreign antigen that becomes a tolerogen does so conditionally (only does so at a certain amount of antigen concentration, for example)
What are antibody constant regions
These are CsubH and CsubL. Only CsubH does any effector functions (binding to Fc receptors, binding complement)
How do B cells get activated (in general)
They need T cell help, because antigens cannot cross-link the BCR on their own
without the T cell, they will become anergic or induced to apoptosis
What do Treg cells express (3)
CD4, CD25, FoxP3
What are “Bare Lymphocyte Syndromes”
“Bare Lymphocytes” are lymphocytes without class I or class II MHC. So, “Bare Lymphocyte Syndromes” refer to a MHC class I or MHC class II deficiency
What is immunogenic tolerance
Immunogenic tolerance is unresponsiveness to an antigen
this can be to self-antigens (self-tolerance) or foreign antigens
self-tolerance is part of the normal immune system education
What kind of epitopes are recognized by T cells
linear determinents of amino acids only
length limited by MHC binding (MHC I = 8-11, MHC II 10-30)
Why do SNPs matter to allergists
several predispose to higher risk of atopy and differing response of medications for allergic processes
Hapten
small-molecule antigen that, when bound to a larger carrier such as a protein, is capable of eliciting the production of antibodies; hapten-specific B cells interact with carrier-specific T cells to generate these antibodies; once an antibody to a hapten is generated, the carrier is no longer needed to simulate an immune response
What mutation occurs in IPEX
FoxP3 mutation, as in IPEX, causes immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome
fatal autoimmune disorder characterized by triad of watery diarrhea, eczema, and endocrinopathy
Sos
a GDP/GTP exchanger
in the attached picture, the SOS is simply termed the “GDP/GTP exchange factor”, but is in fact the same thing
What signaling molecule is required for T-lymphocyte activation and maturation (both CD4 and CD8)
Lck
(part of a Src family tyrosine kinase)
phosphorylates the ITAMs in CD3 and zeta proteins so that ZAP protein is recruited
What is the definition of “antigen”
any substance that gives rise to a specific immune response or is recognized by lymphocytes or antibodies
T/F T cells recognize lipids, nucleic acids, polysaccharides that are presented by MHC molecules
F, these entities are not presented by T cells and are thus not recognized by T cells
How does receptor editing work
This involves reactivation of RAG1 and RAG2 when a high-affinity self-antigen is recognized by the BCR
The RAG enzymes will delete the previously rearranged VJ exon and give the BCR a new light chain. As a result, this self-reactive B cell will have a new specificity.
If this next recombination recognizes self too - the B cell will be deleted by apoptosis, or possibly just become anergic if the self-antigen is of low concentration
CRAC
calcium release activated calcium channel, on the cell membrane
it’s necessary for more calcium to come in the cell for various PKC transcription factors to come into being (notably NFAT)
Review the Functional Features of IgG
For the Filaggrin gene, name the associated protein, the protein function, and relevance in atopy
Filaggrin, essential for epidermal barrier, increased risk of eczema/asthma
What are some differences between alpha beta and gamma delta T lymphocytes
gamma delta cells do not have CD4 or CD8
they are NOT HLA RESTRICTED
they are a bridge between innate and acquired immunity
What are adjuvants
molecules given in vaccines to enhance the body’s immune response to an antigen; typically this involves activating the innate immune system leading to costimulatory expression/cytokine production leading to an adaptive response
For the 17q12-21 gene, name the associated protein, the protein function, and relevance in atopy
ORMDL3, unknown function, increased risk of asthma
calcineurin
activator of nuclear factor of activated T lymphocytes (NFAT) by dephosphorylation, allowing it to travel to the nucleus
Antigen is a contraction of what two words?
Antibody Generator
review “types of mutations”
Key Facts
What is the only Ig to cross the placenta
What is the Ig with highest plasma concentration
What is the Ig with the highest whole body concentration and daily production
What secretes the poly-Ig receptor
IgG (binds to neonatal FcRn)
IgG
IgA
synthesized by the mucosal epithelial cells and helps transport IgA via vesicles to the luminal surface
Which nucleotides are in RNA
The same as DNA, but there is uracil (U) instead of T
A, G, U, C
Where in the body does central tolerance occur
Central tolerance occurs in the lymph organs (thymus for t cells, bone marrow for b cells)
Key Fact - What IgG subclass has the shortest half-life
IgG3
How do nucleotides fit together as far as base pairing
A clicks with T
G clicks with C
Review the structure of class I and class II molecules
LAT
phosphorylation of LAT recruits adapter proteins that mediate different signaling pathways
What enzyme is stimulated with CD40L-CD40 interactions
stimulates activation-induced cytosine deaminase (AID), crucial for somatic mutation and isotype switching
What is a mutation
a change in the nucleotide sequence of genes
What cells have MHC class II
APCs - dendritic cells, macrophages, B cells
What are the three toxins associated with Staph Aureus superantigen disease
SEB - food poisoning SEC2 - food poisoning TSST - toxic shock syndrome
What are SNPs
single nucleotide polymorphism, widely used in GWAs (genome-wide association studies)
this is a variation in DNA sequence that occurs when a single nucleotide differs from the normal
What kinds of epitopes are recognized by B cells
linear determinants or tertiary structure in native conformation
carbohydrates, amino acids, nucleic acids, phospholipids
Calmodulin
ubiquitous, calcium-dependent regulatory protein that binds calcium and interacts with calcineurin
what is Rheumatoid factor
antibody against the Fc portion of IgG. It is most commonly IgM but it can be any other isotype
What does HLA-DM have to do with MHC class II
HLA-DM is an intracellular protein involved in class II antigen processing. It removes CLIP and thus allows antigenic peptides to be loaded in the MHC binding cleft.
It is not a component of MHC class II
Fyn
Src family kinase, noncovalently associated with CD3
fyn is attached physically to the CD3 proteins in T cells
What do activated CD8 cells do
they become cytolytic
T/F Class switch recombination changes the V but not the C regions
False
Where in the cell is DNA stored (easy question)
nucleus
What is the key component of humoral immunity and what produces it
Igs - produced by B lymphocytes and plasma cells
Are SNPs mutations
these are not considered mutations, as they occur more frequently in noncoding DNA sequences and also occur more often than mutations
What is anergy
Anergy is a state of unresponsiveness to antigenic stimulation; the antigen is recognized by the immune cell but weak signaling (owing to a lack of costimulation) leads to anergy
What is SLAM and why is it important
SLAM (signaling lymphocytic activation molecule) binds to SLAM-associated protein (SAP) which links it to Fyn.
Fyn is linked to CD3 proteins in T cells
so, basically, SLAM is necessary for T-cell signaling
how are germ-line mutations passed down
via reproductive cells
What kind of chemical binding is used in antigen recognition by Ig
reversible, noncovalent binding through the Ig V regions
antibody binds to effector cells through the Fc region
what molecule, downregulated with chronic antigen recognition, leads B-lymphocytes home to lymph nodes to interact with T cells
CXCR5
Polysaccharide Antigens
What immune cells are involved (4)
What is the B-cell response? (4)
Prototypical vaccines (2)
Immune cells = Marginal zone B cells, B-1 cells, Macrophages, “T-cell-independent”
B-cell response = no isotype switch, no affinity maturation, limited memory response, predominantly IgM
Vaccines = MSPV4 (Menomune), PPSV23
What are SNPs useful for
these tend to differ between different geographic and ethnic groups, so they are useful as markers for human genetic variations between groups and their differing susceptibility to various diseases
What protein is key in T cell apoptosis
BIM - proapoptotic member of the Bcl-2 family. Leads to apoptosis via mitochondrial pathway
Ribi adjuvant system
Squalene-Tween80-water and oil emulsification
What type of molecule combines with protein to make ribosomes
rRNA
What processes maintain peripheral T-cell anergy at the cellular level
blockade of TCR signalling, ubiquitin ligases (which target proteins for degradation), and inhibitor costimulatory molecules (CTLA4, PD-1)
Key Fact - On what chromosome are MHC molecules coded
What are the three regions that on this chromosome that encode the MHC
Chromosome 6
Class II, Class III, Class I
What is an epitope
Antigenic determinant. It is the antigenic component identified by a unique antibody. A single antigen may have many different epitopes.
What receptor enables NK-T cells to recognize lipids
CD1
What do accessory molecules for the TCR contain
immunoreceptor tyrosine-based activation motifs (ITAMs)
Incomplete Freund’s adjuvant - what is it
water in oil emulsificaton
what is transcription? What is translation?
transcription is synthesis of mRNA from DNA
translation is the synthesis of proteins from mRNA
Aluminum adjuvant - where is it used
used commonly in humans
What is a “carrier”
a macromolecular substance to which a hapten is coupled in order to produce an immune response against the hapten
ERK
one of the MAP kinases that activates the transcription factor activation protein 1 (AP-1)
Review characteristics of bare lymphocyte disorders
How are Ig fragments produced
Papain cleaves Ig above the hinge, and results in two Fab (antigen-binding) fragments and 1 Fc (crystallizable fragment)
Pepsin cleaves Ig below the hinge at multiple sites
How is tolerance maintained to self by the innate immune system
this occurs via the dendritic cells. Immature/nonactivated dendritic cells still present self-antigen on their surface. These presentations don’t happen with any costimulation so the T cells don’t get a second signal, which results in continued tolerance.
Review the MHC class I antigen-processing pathway
What is another name for MHC molecules
human leukocyte antigens (HLA)
For the Xp22 gene, name the associated protein, the protein function, and relevance in atopy
TLR 7 and TLR 8, pattern recognition receptor for viral ssRNA, increased risk of asthma/rhinitis/atopic derm and increased specific IgE
What are the two main factors that determine T cell tolerance or negative selection in the thymus
antigen concentration and antigen affinity to the TCR
high concentration and high affinity promote negative selection
What antibody type fixes complement the best
IgM
At the molecular level, where do superantigens bind the T cell
Superantigens bind the variable portion of the Beta chain of TCR (CDR4) that are outside of the peptide-binding groove on the MHC molecule
What is a conjugated vaccine
What are some examples
T-independent antigens linked to a carrier protein, which can trigger T-dependent response and memory.
Examples are 13-valent pneumococcal vaccine (Prevnar 13), Hib vaccine, and meningococcal vaccines (MCV4-Menactra and Menveo)
IRAK4
activates NFkB, recurrent pneumococcal disease, think severe pneumococcal infections without fever
MYd88 is similar
anhidrotic ectodermal dysplasia is associated with what mutation
NEMO
Review 95% PPV for failed food challenge (its actually 75% for soy and wheat)
Continued - review 95% PPV for failed food challenge (its actually 75% for soy and wheat)
What INS is best studied/safest in pregnancy
Rhinocort (Budesonide)
Fluticasone is ok, too
