Immunology Flashcards
Pattern-recognition receptor (PRR) and Toll-like Receptors (TLR)
PRRs are located on the surface of most body cells; they recognize various classes of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)
TLRs are a class of PRRs often found on WBCs, blood vessel endothelial cells, etc.
Especially important on DCs enabling activation of innate immune response
NFKB
The final transcription factor most commonly activated by TLR activity; mediates inflammation pathway
Mechanism of innate immunity
Dendritic Cells (DCs) located in mucous membranes recognize and ingest foreign molecules via phagocytosis; they migrate through the lymphatic system to the nearest draining node where they present the antigen via MHCII to a diverse population of lymphocytes; specifically activated lymphocytes divide and give rise to a clonal population of activated cells
General function of T cells
T cells recognize antigens that are presented by DCs; activated T cells proliferate, giving rise to a clonal population of daughter cells that travel throughout the body to places where the antigen has invaded; there, they are re-stimulated by local antigen-presenting cells to release lymphokines
General role of B Cells
B cells recognize antigens via surface receptors and become activated, with help from Tfh cells, to proliferate and produce soluble antibodies released into body fluids
Type I Immunopathology
Immediate hypersensitivity caused by overproduction of IgE in response to environmental antigen; IgE binds mast cells, triggering the release of Histamine
Type II Immunopathology
Autoimmunity
Type III Immunopathology
Occurs when an individual makes an antibody against a soluble antigen and the antigen-antibody complex, instead of being consumed by phagocytes, becomes trapped in the basement membrane of capillaries, activating the inflammatory response
Type IV Immunopathology
T-cell mediated tissue damage
Chronic frustrated immune response
Inappropriate activation of the immune response against endogenous foreign antigens, i.e. gut bacteria
Cytokines and chemokines
Small proteins released following TLR activation via NFKB pathway to produce inflammation
Mechanism of innate immunity
Dendritic Cells (DCs) located in mucous membranes recognize and ingest foreign molecules via phagocytosis; they migrate through the lymphatic system to the nearest draining node where they present the antigen via MHCII to a diverse population of lymphocytes; specifically activated lymphocytes divide and give rise to a clonal population of activated cells
General function of T cells
T cells recognize antigens that are presented by DCs; activated T cells proliferate, giving rise to a clonal population of daughter cells that travel throughout the body to places where the antigen has invaded; there, they are re-stimulated by local antigen-presenting cells to release lymphokines
Lymphocyte Recirculation
Lymphocytes circulating in the blood encounter high, cuboidal endothelial cells lining the postcapillary venules in the peripheral lymph nodes; lymphocytes pass between these endothelial cells into the body of the lymph node where they may stay or move into the lymph, which eventually drains into the venous blood
IgG
2 light chains + 2 gamma chains
Main antibody in blood; appears after IgM following immunization but concentrations go higher and last longer; activates complement; the only antibody class that can cross the placenta from mother to fetus
IgE
2 light chains + 2 epsilon chains
Mediates the immediate hypersensitivity (allergic) response; IgE Fc region binds to a receptor on mast cells triggering release of histamine
IgD
2 light chains + 2 delta chains
Receptor on B cells
IgA
2 basic units (4 light chains + 4 alpha chains) held together by a J chain and wrapped in Secretory Component
“First line of defense” - main antibody of fluid secretions; Secretory Component protects IgA from proteolysis by digestive enzymes
IgM
5 basic units (10 light chains + 10 mu chains) held together by a J chain; decavalent
The first antibody to appear in the serum after immunization; activates complement
Complement - Classical Pathway
After IgG or IgM binds antigen, a chance in Fc allows binding and activation of C1q; C1q must interact with 2 Fcs simultaneously in order to become activated, either by binding two IgGs on the same antigen or by interacting with a single IgM
C1 activates C4 and then C2, which together activate C3, which activates C5, C6, C7, C8, C9
Accumulation of C3b - C9b on the pathogen membrane forms a transmembrane pore (Membrane Attack Complex) leading to cell lysis
Which components of complement are lytic?
C3b - C9b accumulated on the pathogen membrane to form the membrane attack complex, a transmembrane pore leading to cell lysis
Which components of complement are chemotactic?
Soluble C5a is chemotactic for PMN cells
Which components of complement are opsonizing?
C3b on the pathogen surface interacts with C3b receptors on the cell surface of PMNs; C3b makes the pathogen more easily recognizable and digestible by phagocytes
Which components of complement are anaphylotoxic?
Soluble C5a can interact with receptors on the surface of mast cells, inducing them to release histamine
Complement - Alternative Pathway
Activated by IgA antigen complexes and by certain cell wall structures of microorganisms which activate complement even in the absence of an antibody response
C3 activates C5, then C6, C7, C8, C9
Complement - Lectin Pathway
The lectin pathway is mediated by mannose-binding protein (MBP) which binds carbohydrates on pathogen cell surfaces; MBP is functionally similar to C1q in the classical pathway
MBP activates C4, then C2 and C3 activates C5, which activates C6, C7, C8, and C9
Cross reactivity
The tendency of an antibody to react with more than one antigen
Ex: Streptococci bacteria cross reacts with an antigen found on heart valves; streptococci infection may activate B cells against heart valves causing complement-mediated rheumatic heart disease
Allotypic Exclusion
The process by which any individual B cell expresses only one H chain and one L chain, despite the presence of multiple copies of each; the rest of the genes are silenced (“excluded”)
Mechanism of V(D)J Recombination
First, a random D segment is brought together with a random J segment and spliced; next, a random V segment is brought together with the DJ segment and spliced; the entire region of DNA is assembled including the V(D)J unit and the constant region including the mu and delta constant region
These primary RNA transcripts are alternatively processed to make either VDJ-mu (IgM) or VDJ-delta (IgD)
When a cell wants to produce IgG, IgA, or IgE it returns to the recombined DNA constiting of the linked VDJ region and the constant region and cuts out the intervening constant sequences via splicing
Somatic recombination of antibodies - mechanism
The process by which cells increase antibody diversity through random “sloppiness” of V(D)J Recombination
Exonucleases randomly chew away a few nucleotides prior to (D)J and V segments are joined; terminal deoxynucleotidyl transferase (TdT) adds several random nucleotides to the sequence at the joining region (the N region)
2/3 times this process results in a nonsense (stop) codon and B cell destruction
Affinity maturation
Hypermutation occurs in the CDR regions of antibodies during rapid B cell division, producing both higher-affinity and lower-affinity daughter cells; over time, lower-affinity antibodies are culled and the immune response to a specific antigen improves
Cross reactivity
The tendency of an antibody to react with more than one antigen
Ex: Streptococci bacteria cross reacts with an antigen found on heart valves; streptococci infection may activate B cells against heart valves causing complement-mediated rheumatic heart disease
Allotypic Exclusion
The process by which any individual B cell expresses only one H chain and one L chain, despite the presence of multiple copies of each; the rest of the genes are silenced (“excluded”)
Mechanism of V(D)J Recombination
First, a random D segment is brought together with a random J segment and spliced; next, a random V segment is brought together with the DJ segment and spliced; the entire region of DNA is assembled including the V(D)J unit and the constant region including the mu and delta constant region
These primary RNA transcripts are alternatively processed to make either VDJ-mu (IgM) or VDJ-delta (IgD)
When a cell wants to produce IgG, IgA, or IgE it returns to the recombined DNA constiting of the linked VDJ region and the constant region and cuts out the intervening constant sequences via splicing
Somatic recombination of antibodies - mechanism
The process by which cells increase antibody diversity through random “sloppiness” of V(D)J Recombination
Exonucleases randomly chew away a few nucleotides prior to (D)J and V segments are joined; terminal deoxynucleotidyl transferase (TdT) adds several random nucleotides to the sequence at the joining region (the N region)
2/3 times this process results in a nonsense (stop) codon and B cell destruction
Affinity maturation
Hypermutation occurs in the CDR regions of antibodies during rapid B cell division, producing both higher-affinity and lower-affinity daughter cells; over time, lower-affinity antibodies are culled and the immune response to a specific antigen improves
Allotype
Minor allelic differences in the sequence of immunoglobulins between individuals, determined by parental allotypes via Mendelian inheritance
Idiotype
The unique combining region of an antibody, made up of the sequence of CDR amino acids of its L and H chains
Pro B Cell
The earliest B-cell line differentiated cell found in the bone marrow; contains mu chains in the cytoplasm
Pre-B cell
Characterized by the presence of cytoplasmic IgM but no surface expressed IgM
Immature B cell
Contains both cytoplasmic and surface IgM but no IgD
If these cells become activated against antigen in the bone marrow they may undergo receptor editing and further maturation OR undergo clonal abortion
Mature B Cell
Contains both surface IgM and IgD of the same specificity
Bursa of Fabricius
In birds, this is the organ where B cells finish their development; it is located in the hind end of the gut
Humans have no Bursa of Fabricius; B cell differentiation takes place in the bone marrow
IgM in fetuses & newborns
Fetuses make IgM in utero starting around 3 months gestation; any IgM seen in fetal circulation in utero must have been produced by the fetus because IgM cannot cross the placenta
IgG in fetuses and newborns
Fetuses do not make IgG in utero and so any IgG seen in fetal circulation must have come from the mother, actively transported across the placenta; newborns start making their own IgG around ~3 months
Babies are particularly vulnerable to infection 3-6 months of age when maternal IgG has declined but their own IgG production has not ramped up yet
Premature babies born before 39 weeks gestation miss out on the sharpest spike in maternal IgG production and may be born immunocompromised
How do Th0 cells become activated?
Through a “two hit” model:
- The Th0 cell binds the antigen-presenting dendritic cell via its TCR/CD3 complex
- The dendritic cell secretes IL-12, which helps to activate Th0
Function of Th1
Secrete IFN-y, which activates M1 macrophages through the classical pathway; M1 macrophages phagocytose foreign material
Secretes IL-2, which activates CTLs
Function of Th17
Activates M1 macrophages through the classical pathway
Function of Th2
Releases IL-4, which activates M2 macrophages through the alternate pathway; M2 macrophages participate in tissue healing and walling off of pathogens
IL-4 is also chemotaxic for eosinophils
Function of Tfh
Activated Tfh migrate to the lymph node follicle where they stimulate B cells to secrete antigen and facilitate antibody class switching from IgM / IgD to IgG, IgA, and IgE
Function of Treg
Releases TGF-B and IL-10, which function to negatively regulate the immune response by inhibiting Th0
Activation of CTLs
CTLs are activated by antigen-presenting dendritic cells and also by IL-2 secreted by Th1
Functions of CTLs
CTLs induce apoptosis by 2 mechanisms:
- CTLs express CD95L, which interacts with CD95 on the surface of target cells to induce apoptosis
- CTLs secrete proteases called granzymes and perforins, which allow penetration of granzymes into the cell, causing apoptosis
Structure of TCRs
TCRs are comprised of two transmembrane domains, alpha and beta; each chain has 3 CDRs
TCRs associate closely with CD3 on the surface of all T cells, which facilitates its binding interactions with antigens
Cross-presentation
Dendritic Cells can present antigen on either MHC-I or MHC-II, allowing DCs to activate both CTLs and Th cells simultaneously
How do Thf cells activate B cells?
B cells take up, digest, and present a piece of their specific antigen on MHC-II, which is recognized by Tfh cells; Tfh then directs specific activating signals toward the B cell, inciting it to release antibody or undergo class switching
T cell independent antibody response
Some antigens do not require T cell help to produce an immune response; these are mostly carbohydrates with the same epitope repeated over and over, which can bind multiple sites on IgM
Since no T cells are involved class switching cannot occur and the immune response is mediated entirely by IgM
Even individuals who are extremely T cell deficient can make some immune response to carbohydrates
Mitogen
A molecule that stimulates T cell division
ex: Phytohemagluttinin (PHA), Pokeweed mitogen
AIRE
Autoimmune regulatory element; responsible for the presence of otherwise out-of-place peptides in the thymus which help facilitate negative selection of developing T cells that are auto-reactive against a wide variety of self peptides
Positive Selection of T Cells
Occurs via interactions between alpha and beta CDRs 1 and 2 with MHC-I (for CTLs) or MHC-II (for Th cells)
HLA Alleles by Class
Class I: B / C/ A
Class II: DP / DQ / DR
One way MLR
Donor leukocytes are treated with radiation to kill dividing T cells, while leaving donor macrophages with MHC-II intact; donor leukocytes are mixed with recipient leukocytes; any growth in T cell division is the result of recipient T cells activating against donor MHC-II
H-Y
H-Y is an internal protein coded for on the Y chromosome whose peptides are displayed on MHC-I of all male cells; because of H-Y, male skin gracts will be slowly rejected by females, while males can accept female skin grafts
Hyperacute graft rejection
Occurs if a graft is given to a patient who has a preexisting antibody, IgG or IgM, to it (either to its HLA because of prior graft or, in a mismatch, to ABO blood group antigens)
Mechanism of graft rejection
Th1 cells recognize foreign HLA-DR on graft cell macrophages causing them to proliferate and secrete IFN-y, which activates M1 macrophages;
Meanwhile, CTLs recognize HLA-A and HLA-B (Class I) on all graft cells; however, this recognition is usually insufficient to activate CTLs without the help of Th1-derived IL-2 as a second signal. Once activated, CTLs start directly killing graft cells.
Why is DR the most important histocompatibility locus?
If DR is identical between donor and recipient then Th1 cells will not be activated; as a consequence, few M1 macrophages will be activated, no IL-2 will be generated, and few CTLs will be activated
Ankylosing Spondylitis
An arthritic condition involving inflammation of the tendons and fibrous joints, leading to calcification and inflexibility of the joints
92% of people with AS are HLA-B27; the current model suggests that rare self-modification of proteins may create novel epitopes that associate strongly with certain MHC alleles; the T Cells that respond to these “neo-antigens” cross-react with the normal protein
Types of Immunity
Natural / Active - immunity resulting from exposure to disease
Natural / Passive - immunity transferred from mother to fetus (IgG across placenta, IgA in breastmilk)
Artificial / Passive - anti-serum (serum containing purified antibodies, already produced)
Artificial / Active - vaccination (synthesized antigen presentation), allows body to produce antibody
Tetanus Immunization
Tetanus toxin is so toxic that it cannot be safely administered; tetanus toxoid (inactivated toxin) resembles the toxin enough to produce immunogenic response
Antibiotics are only partially effective against tetanus because its the release of toxin, not the growth of bacteria, that is responsible for pathology
Antitoxin (human tetanus immune globulin) can be used but is not widely available
Conjugate vaccines
Created by covalent linkage of a poor antigen (usually polysaccharide organisms that activate T-cell independent immune response) with a carrier protein from the same micro-organism to which Tfh cells can respond and help focus the B-cell response
Adjuvant
Substances added to vaccines to make them more immunogenic
Mechanism: Adjuvants mimic PAMPs and thereby help cause an innate immune response through activation of DCs and subsequent Tfh proliferation
Ex: Alum
People deficient in complement are susceptible to infection by what organism?
Neisseria Gonorrhoeae
Left Shift
Leukocytosis with an increase in the number of immature leukocytes in the blood, particularly bands (neutrophils)
Schilling Test
Tests for pernicious anemia due to B12 malabsorption;
Radiolabeled B12 is given orally and is followed by IM injection of B12 to saturate B12 receptors in the tissue so that any radiolabeled B12 that is absorbed from the gut is excreted into the urine.
A normal result shows at least 10% of the radiolabeled vitamin B12 in the urine over the first 24 hours.
Which part of the membrane attack complex polymerizes to form a transmembrane channel?
C9
What is the half life of maternal IgG?
3 weeks
Live attenuated vaccines
MMR
Flu nasal spray
Chicken Pox
Rotavirus
Only to be given after 1 year age
What is an average value for cellularity?
100 - age (%)
