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44 Cards in this Set

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List Ig classes and subclasses and their respective heavy chains.
IgM -µ heavy chain -> Ab induced in primary response
IgG -γ heavy chain -> IgG1, IgG2, IgG3, IgG4-> Ab induced in secondary response
IgE - ε heavy chain -> allergic hypersensitivity
IgA - α heavy chain -> IgA1, IgA2 -> Ig in external secretions
IgD - δ heavy chain -> found on the surface of B cells (w/IgM)
Define domain and hinge region
the immunoglobin domain is a series of repeating homologous units of light chain and heavy chains that are each about 110 amino acids residues in lenght which fold independently in a common globular motif

a hinge region of antibody molecules is a flexible domain that joins the Fab arms to the Fc region. Flexibility of hinge region allow the Fab arms of IgG and IgA to adopt wide angles permitting binding epitopes spaced variable distances apart.
Define V domain and C domain
V domains are the variable region of a polypeptide chain of an Ig or T-cell receptor. This region is composed of a single amino terminal. Paired V domains from the antigen-binding site. Must undergo VJ or VDJ rearrangement.

The constant domain of an Ig or T-cell receptor is a constant region of aa sequence between diff. molecs. Constant region determines its effector fx.
Compare the similarity of heavy and light chain domains of antibodies of diff specificities
IgM H chains have 4 CH domains, 1 VH domain; are CHO rich
IgG H chains have 3 CH domains, 1 VH domain.
IgD H chains have 3 CH domains, 1 VH domain
IgE has 4 CH domains and 1 VH domain CHO rich
IgA H chains have 3 CH domains and 1 VH domain.
L chain has 2 domains: 1 Vι domain and 1 Cι domain. The light chains fall into 2 classes κ and λ.
H chain has either 4 or 5 domains: 1 VH domain and 3 or 4 CH domains.

IgM and IgE has an extra C domain: 1 VL and 1 CL + I VH + 4 CH domains. and no hinge region.
Define variability plot, framework regions and CDR regions
A variability plot is one in which the aa sequences of many diff Ab V regions are compared. There are 3 hypervariable regions in both VH and VL regions.
In VH HV1 30-36 HV2 49-65 HV3 95-103
In VL HV1 28-35 HV2 49-59 HV3 92-103
HV3 is the most variable in both chains.
The framework regions from the β sheet that provide the structural framework of the domain and the HV sequences form 3 loops at the edge of the β barrel.
The HV loops from each region form the Ab binding site so there are a total of 6 HV loops. Also called the complementarity-determining regions. Six CDRs 3 from each chain.
2 loops 1 from each chain form the binding site.
Identify the regions of IgG that comprise Fab and Fc fragments
The antibody molecule can be cleaved into functionally distinct fragments Fab Fragment antibody binding and Fragment crystallizable. Fab is VH and VL and CL and CH1.
Fc is made up of the paired CH2 and CH3. The Fc portion interacts with effector molecules. The functional diff btwn heavy chain isotypes lie mainly in the Fc fragment.
Identify major effector fx of each Ig isotype
IgM: Ab of primary response and major class of Ab elicited by T-independent antigen (polysaccharide), complement fixation by classical pathway.
IgG: Ab class of secondary response for most proteins (T dependent) Ag. Crosses human placenta.
IgD: B-cell Ag receptor along with IgM. usually membrane bound.
IgE: allergic hyperpersensitiveness. IgE Ab fix to mast cells and basophils via an Fc receptor on the cells.
IgA is predominant class in external secretions. Key role in mucosal immunity.
Compare the relative levels of each Ig class in serum and in secretions
IgG serum conc. ~ 1200mg/dl
IgA serum conc. ~ 300mg/dl
IgM serum conc. ~ 100mg/dl
IgD serum conc. ~ 3mg/dl
IgE serum conc. ~ .03mg/dl

Lowest serum conc. is IgE.
Highest serum conc. IgG

IgE .03< IgD 3<IgM 100<IgA 300<IgG 1200
Define Fc receptors
Fc receptors are on immune effector cells such as mast cells for IgE producing an allergic inflammatory response. Fc receptors bind the Fc portions of Ig isotypes.
State the relationship of VH to VL in the 3D structure of Ig
VH and Vι come together to form the antigen binding site.
Define epitope as it relates to protein antigen
An epitope is a site on an Ag recognized by an Ab or an Ag receptor. Epitopes are aka antigenic determinants.

A T-cell epitope is a short peptide derived from a protein antigen. It binds to an MHC molecule and is recognized by a particular T cell.
B-cell epitopes are antigenic determinants recognized by B cells and are typically discontuous in the primary structure.
Contrast the genetic basis of isotypes and allotypes
Proteins that reflect genes common to all members of a species. Eg. each of us has a gene for the IgG1 heavy chain constant region. So different isotypes have different constant regions. IgG and IgA are isotypes because they have different constant regions.
Allotypes-> allelic polymorphisms. Your Ig κ light chains may differ from mine in constant region by a few aa; these diff reflect alleles ~ alternate forms of a gene.
These genetic variants of a protein can be detected by allotype-specific Ab.
You may be htereozygous for the gene for C κ locus i.e. you inherited 1 allele from mom and a diff allel from dad. Both alleles are expressed in diff cells. They are codominant.
Explain how anti-idiotype antibody can be used to treat B-cell lymphoma.
An idiotype is one which has unique binding sites-> diff variable regions.
If a rabbit is immunized with Idiotype B to made anti-idotype B Ab.
B Lymphoma: Expansion of a single clone of B cells with same VH and VL regions (i.e same idiotype)
Treatment with anti-idiotype antibody would only affect this specific clone of B cells.
The Fc portion of the γ-heavy chain has how many domains?
The Fc portion o fthe ϒ-heavy chain has 2 domains. CH2 and CH3
What genes cconstitute Major Histocompatibility Complex Class I loci?
Class I loci:
Human leukocyte antigens -> HLA A, HLA B, HLA C
found on all nucleated cells
present antigen to CD8+ T lymphocytes
What is the physiological function of MHC?
MHC gene products -> Class I and Class II present peptides to T lymphocytes by sampling intracellular pools of peptides and presenting them on their surface to T lymphoctyes.
What genes cconstitute Major Histocompatibility Complex Class II loci?
Subset loci: DR, DQ, DP
found on Dendritic cells, B-lymphocytes and macrophages
present antigen to CD4+ lymphocytes
What genes cconstitute Major Histocompatibility Complex Class III loci?
Each person has 2 haplotypes, with codominant genetic expression. Explain.
Each individual expresses in a co-dominant fashion class I and class II genes of both chromosome 6.
Each person expresses 3 paternal and 3 maternal class I as well as 3 paternal and 3 maternal class II
Each person has 2 "half sets" (haplotypes) inherited from each parent.
Both of these haplotypes are expressed equally.
What is MHC restriction?
the dependence of T cells specific reactivity on foreign Ag plus MHC products ie class I or II products rather then foreign Ag alone
What are the 3 main effector functions of the Fc portions of antibodies?
1) Fc of certain isotypes are recognized by Fc receptors on immune effector cels. IgG1 and IgG3 are recognized by Fc receptors on phagocytic cells. IgE Fc binds Fcε on inflammatory mediators (allergy).
2) Fc portion of Ag:Ab complexes can bind to complement and initiate complement cascade.
3) Fc portion can deliver antibodies to places they wouldn't reach without active transport. such as mucous secretions, tears and milk ->IgA and fetal blood -> IgG.
Id the approx no. of H chains V, D and J gene segments in the germline.
Heavy Chain has
approx. 40 V gene segments
approx. 25 D gene segments
approx. 6 J gene segments
The number of functional gene segments in human Ig loci was found by exhaustive cloning due to genetic polymorphism the numbers will not be the same for all people.
Id the approx. no. of L chain V and J segments in the germline.
Light Chain has κ and λ light chains.
κ chain has approx. 40 V gene segments
κ chain has approx. 0 D gene segments
κ chain has approx. 5 J gene segments

λ chain has approx. 30 V gene segments
λ chain has approx. 0 D gene segments
λ chain has approx. 4 J gene segments
List the order of Ig H and L chain gene rearrangements.
DNA rearrangements occur in a precise order and occur INDEPENDENT of antigen stimulation.
1) Heavy Chain - DJ -> D and J segments join & intervening DNA deleted.
2) Heavy Chain - VDJ -> V is joined to DJ = VDJ. All other D regions 5' upstream are deleted. Intron still between VDJ and C region.
Transcription occurs
3) Primary transcript produced
4) Intron between VDJ and C region spliced.
5) mRNA translated -> polypeptide chain produced.

Light chain VJ somatic rearrangement -> Intron remains between VJ and C region. -> Primary transcript made -> intron between VJ and C is spliced -> translation -> polypeptide chain.
Define allelic exclusion
refers to the fact that in a heterozygous individual, only 1 of the alternative C-region alleles of the heavy or light chain is expressed in a single B cell and in an Ig molecule.

Only 1 IgH and 1 IgL allele are productively rearr. This expression of only one allele in a cell is termed allelic exclusion. Although DJ rearr occurs on both alleles in a cell, only 1 allele has a functional VDJ gene.
How long does it take to an individual's serum immunoglobin to reach adult levels?
IgG at birth the baby has 100% of adult levels of IgG from mom. At 4 years old the adult levels of the individuals OWN IgG are reached.

IgM reaches adult levels at about 10 months.
IgA at about 10 years of age
IgG at about 4 years of age

The period when the individual is most vulnerable is from 3 months to 1 year when IgG levels are transiently low.
State the molecular basis for allelic exclusion
polymorphsims of the constant regions of the Ig heavy-chain and light chain genes known as allotypes -> In rabbit A, Ig Heavy chain locus a/a, IgA will be expressed. In rabbit B, IgH b/b, IgB will be expressed. In rabbit AB IgH a/b. Individual B cells carry either IgA or IgB but individual B CELLS DO NOT CARRY IgA and IgB. This allelic exclusion reflects the productive rearr of only one of the two parental Ig Heavy Chain alleles.
Given a B Cell w/ a VDJ gene rearrangement describe the fate of:
1. VH gene segments upstream of the VDJ gene
2. D gene seg. that weren't used in the VDJ rearrangement.
3. J gene segment downstream of the VDJ gene.
VH gene segments upstream of the VDJ gene are deledted
D gene segments that weren't used in the VDJ rearr were deleted
J gene segments downstream of the VDJ gene are deleted
Describe how the heptamer/nonamer recombination signal sequences (RSS) mediate V, D & J gene rearrangements.
The heptamers and nonamers guide DNA rearrangement.
Juxtaposition of RSSs results in looping out of the intervening DNA. Recombination occurs at the ends of the heptamer sequesnces in the RSSs creating a signal joint and releasing the intervening DNA in the from of a closed circle BREC.
In other cases, V and J gene segments are initially oriented in opposite transcriptional directions. Looping out DNA by joining the 2 heptamer seq. results in the inversion and integration of the intervening DNA. V and J joining creates a fx V-region.
heptamer 5' CACAGTG 3'
nonamer 5' ACAAAAACC 3'
separated by spacer 12/23 ~ 1/2 turns of DNA double helix
An RSS with a 12 nt spacer can only be joined to a 23 nt spacer and vice versa
State the role of RNA procession in synthesis of Ig L chains.
RNA processing -> splicing the primary transcript RNA deletes the intron between VJ and C regions to make a mRNA reading for translation into Ig L chains.
For the light chain genes, compare the intervening nucleic acid seqs. that are lost during DNA recomb. with those lost during RNA splicing.
During RNA splicing introns are lost, these are non-coding DNA. The DNA lost during DNA recombination were coding regions for example J regions or V regions 5' of VJ. This changes the DNA seq.
Compare and Contrast the DNA rearrangements that occur during VDJ gene joining with those during isotype switching.
VDJ joining involve deletions of coding DNA sequences and is independent of antigen. There is no rearrangement of C region. Requires RSS for recombination and RAG1 and RAG2 for DNA cleavage.

Isotype switching occurs during an immune response. Is rearrangement of the CH genes. DNA loops out and is deleted from genomic DNA. Recombination involves an enzyme called AID. VDJ is not rearranged. Once CH genes are deleted VDJ complexes with next 3' CH gene.
AID -> Activation-Induced Cytidine deaminase.
State how μ and δ H chain can arise from the same primary transcript.
μ and δ H chains with the same VH domain result from alternative splicing of primary transcripts. That is same VDJ and different C regions.
Compare the organization of TCR nd Ig genes.
Compare the mechanism of rearrangements of TCR and Ig genes.
TCR genes are similar to Ig genes and are rearr. by the same enzymes.
Ig has light and heavy chains with V and C region
TCR has alpha and Beta chains with V and C region
TCR alpha locus has VJ segments
TCR beta like heavy chains has VDJ

B cell maturation in bone marrow
T cell maturation in thymus

Rearrangment involves looping out of DNA based on RSS heptamer and nonamer. Circular DNA called TREC and BREC in B cells.

Genetic effects affect both equally.
Most T cells have alpaBeta TCR ~ 5% have gamma delta TCR.
Compare the mechanism of rearrangements of TCR and Ig genes.
State the approximate number of antibody specificities needed for protection.
The total number of antibody specificities available to an individual is knows as the antibody repertoire or immunoglobin repertoire

which is at least 10∧11
The number of antibody specificities present at any one time is, however, limited by the total number of B cells in an individual as well as by each individual's encounter with antigens.
State the number of germline VH, VL, D, JH adn JL gene segments.
VH has 40 functional gene segments in the germline
VL has 40 of the κ light chains or 30 of the λ light chains
D has 0 light chain gene segments and 25 heavy chain light segments.
JH has 6 gene segments
JL is 5 for κ light chains or 4 λ light chains
Owing to genetic polymorphisms, the numbers will not be the same for all people.
Explain the mechanisms by which CDR3 becomes more variable than CDR1 and CDR2.
CDR3 are more variable because of the D-D fusion which is found in approx 5% of Ab and is the major mech causing the unusually long CDR3 loops found in some heavy chains.
Compare the contribution of somatic mutation to the diversity of Ig receptors with the diversity of T cell receptors.
Effector fx of B cells depend on secreted antibodies whose diff H chain C region isotypes trigger distinct effector mechanisms.
The effector fx of the T cells in contrast, depend on cell-cell contact and are not mediated directly by the TCR which serves only for antigen recog. C regions of the TCR alpha and beta loci are simpler than tose of the Ig H chain locus. TCR C-region genes encod only transmembrane polypeptides.
see prof about this answer
What is a factor that causes a gene segment to be nonfunctional?
A gene segment is nonfunctional if it incorporates a pseudogene during its rearrangement. A pseudogene is one which has accumulated gene mutation that prevent them from encoding a functional protein.
On what chromosomes are the 3 types of Ig chains found?
λ light-chain locus is located on Chromosome 22
κ light-chain locus is located on Chromosome 2
Η chain locus is located on chromosome 14
How are the C gene region different in each type of light chain compared to heavy chains?
there is one Cκ
there is a single Cλ
and there are a series of C regions arrayed one after the other, each of which corresponds to a diff isotype. B cells initially express IgM and IgD -> alternative splicing. The expression of other isotypes eg. IgG occurs thru isotype switching.
the amount
What is the 12/23 rule?
A gene segment flanked by an RSS with a 12 bp spacer typically can be joined ONLY to one flanked by a 23 bp spacer RSS.
Thus for a H chain, a DH gene segment can be joined to a JH segment and a VH segment to a DH segment but a VH gene segment cannot be joined to a JH segment directly as both VH and JH gene seg are flanked by 23 bp spacers and the DH seg have 12 bp spacers on both sides.
What is the main diff btwn Ig genes and TCR genes?
Effector fx of B cells depend on secreted antibodies whose diff H chain C region isotypes trigger distinct effector mechanisms.
The effector fx of the T cells in contrast, depend on cell-cell contact and are not mediated directly by the TCR which serves only for antigen recog. C regions of the TCR alpha and beta loci are simpler than tose of the Ig H chain locus. TCR C-region genes encod only transmembrane polypeptides.