Flashcards in Basic Pathological Mechanisms March 30-April 3 Deck (71):
What is the role of innate immunity in infection?
Innate immunity can be essentially immediate, since components are pre-formed and exist at sufficient levels prior to the first exposure to a pathogen.
No memory of antigen exposure is required for fast innate immune responses.
What is an example of innate humoral immunity?
alternative or lectin binding pathways of complement activation
What are examples of innate cellular immunity?
macrophages, NK cells, and PMNs
What receptors are used in innate immunity? Describe some of their properties
germ line-encoded receptors (PRRs)
on many cell types (each cell has many different types of these receptors by discrete amounts of specific receptor; may recognize multiple pathogens)
no gene rearrangements
What are ligands for pattern recognition receptors? What is an example?
PAMPs- microbial molecules expressed by a broad set of microbes (so a small number of PRRs suffice to recognize a large number of pathogens)
LPS on many species of gram negative bacteria
What is a characteristic of PAMPs?
critical cell wall components of the microbe (not evolutionary favorable to evolve defenses against human immune system)
Are PRRs differentially expressed through the cell? Give examples
Yes; mannan binding lectin and CRP are secreted (trigger complement)
toll-like receptors and lectins are found on either the cell surface or in the membrane of endosomes/phagosomes (primarily produce cytokines)
NLRs (NOD1 and NOD2) and RNA helicases (RIG-I and MDA-5) are cytosolic (recognize viruses and secrete cytokines)
What is a vaccine adjuvant and what is used today as an adjuvant?
innate activators of APC function
aluminum gels or salts and monophosphoryl lipid A isolated from the surface of bacteria
What is the importance of MHC molecules?
activate T cells; determine outcome of organ transplantation, disease associations
What substance can bind to MHC and TCR to cause toxic shock syndrome?
superantigens produced intracellularly by bacteria and are released upon infection as extracellular mature toxins
What are the three MHC-1 loci? MHC-II?
HLA-A, B, and C
HLA-DP, DQ, DR
Which MHC loci have the most polymorphisms?
DRbeta and B
A haplotype is a set of DNA variations, or polymorphisms, that tend to be inherited together. A haplotype can refer to a combination of alleles or to a set of single nucleotide polymorphisms (SNPs) found on the same chromosome.
humans have two MHC haplotypes (one from mom and one from dad)
What is codominance?
alleles (variants) inherited from both parents are expressed equally
What cells express MHC class 1 receptors?
constitutively expressed on all nucleated cells (not on erythrocytes and neurons)
can be upregulated by interferon alpha or gamma signaling
What cells express MHC class 2 receptors?
constitutively expressed on dendritic cells, B cells, monocytes, and some macrophages ("professional antigen presenting cells")
upregulated by interferon gamma signaling
Describe MHC restriction.
a given T cell will recognize a peptide antigen only when it is bound to a host body's own MHC molecule.
Describe the structure of an MHC class 1 molecule. Which portion of the receptor is not derived from the MHC gene loci?
MHC I occurs as an α chain composed of three domains—α1, α2, and α3. The α1 rests upon a unit of the non-MHC molecule β2 microglobulin
The α3 domain is transmembrane, anchoring the MHC class I molecule to the cell membrane.
The peptide being presented is held by the floor of the peptide-binding groove, in the central region of the α1/α2 heterodimer
Beta sheet is below alpha helixes of from alpha 1 and 2 subunits
present antigens to CD8 T lymphocytes
In terms of structure, where are most polymorphisms found on MHC molecules?
alpha 1, 2, and beta 1 (peptide binding groove)
What are anchor residues?
A few residues in the peptide, called anchor residues, bind to specific pockets on the MHC I, resulting in some specificity of interactions with MHC.
What kind of peptides are bound to class 1 MHC molecules?
8-10 amino acids (no variable extensions beyond amino and carboxy termin of core epitope
Describe the structure of an MHC class II molecule.
MHC class II is formed by two chains, α and β, each having two domains—α1 and α2 and β1 and β2—each chain having a transmembrane domain, α2 and β2, respectively, anchoring the MHC class II molecule to the cell membrane. The peptide-binding groove is formed by the heterodimer of α1 and β1.
T/F MHC class II peptides vary in length but have sequence motifs with anchor residues?
Do MHC molecules discriminate between self and non-self peptides?
Can TCR recognize protein antigens in their native conformation? Can immunoglobulins?
Describe the MHC-1 antigen processing pathway.
partially folded MHC 1 class alpha chains bind to calnexin until beta2 microglobulin binds
calnexin is releases and replaced by chaperone proteins (calreticulin and Erp57); complex binds to TAP via tapasin
cytosolic proteins are degraded to peptide fragments by the protoeasome
TAP delivers a peptide that binds to the MHC class 1 molecule and completes it folding (exported to the plasma membrane)
Describe MHC-II antigen processing pathway.
invariant chain forms a complex with MHC class II, blocking the binding of peptides and misfolded proteins
invariant chain is cleaved in an acidified endosome, leaving a short peptide fragment (CLIP)
endocytosed antigens are degraded to peptides in endosomes, but the CLIP peptide blocks the binding of peptides to class II molecules
HLA-DM binds to MHC class II molecule, releasing CLIP and allowing other peptides to bind (exported to the plasma membrane)
What are roles of the different professional antigen presenting cells?
dendritic cells: prime naive T cells in lymph nodes and spleen
macrophages: present antigen in peripheral tissues (effector response)
B cells: present antigen to T cells, primarily in lymph nodes or spleen (T cells help B cell in isotype switching, affinity maturation, and memory)
Describe Toll-like receptors.
pattern recognition receptors on cell surfaces or in endosomes!!!
All membrane-associated and have similar structure and genetic sequence
Dimerize following binding to ligand for signaling (homo/hetero); NFkappa beta signaling
variable extracellular domain determines binding to ligand
may be localized to endosomes where it scans for viruses (interferon signaling)
What is a mechanism of antigen-presenting cells in preventing immune responses in the absence of pathogens?
Resting (immature) dendritic cells and macrophages have their MHC complexes in internalized vesicles
Activation of macrophages by PAMPs causes translocation of MHC complexes to plasma membrane and synthesis of new MHC complexes
Activation of dendritic cells by PAMPs causes DC maturation resulting in different morphology, upregulation of costimulatory receptors, upregulation of cytokine signaling (receptors); migrate to lymph nodes or secondary lymphoid tissues
Which antigen-presenting cells are the only ones capable of activating naive T cells? Why?
dendritic cells (coactivation mechanisms)
T/F: One MHC molecule cna bind various peptides?
T/F: Class I MHC molecules have fewer polymorphisms than Class II?
T/F: Class II beta chain has fewer polymorphisms than alpha chain?
Do macrophages require coactivors to stimulate T cells?
What part of the MHC class I molecule do CD8 cells bind to?
alpha 3 chain
Describe activation of classical complement pathway.
The classical pathway is initiated by the binding of
the C1 complex to antibodies that are bound to antigens on the surface of bacteria. The C1 complex consists of C1q and two
molecules each of C1r and C1s. The binding of the recognition subcomponent C1q to the Fc portion of immunoglobulins results in autoactivation of the serine protease C1r. C1r then cleaves and activates C1s, which translates the activation of the C1 complex into
complement activation through the cleavage of C4 and C2 to form a C4bC2a enzyme complex. C4bC2a acts as a C3 convertase
and cleaves C3, which results in products that bind to and cause the destruction of invading bacteria.
Describe activation of lectin complement pathway.
The lectin pathway is
initiated by the binding of either mannose-binding lectin (MBL) or ficolin — associated with MBL-associated serine protease 1
(MASP1), MASP2, MASP3 and small MBL-associated protein (sMAP) — to an array of carbohydrate groups on the surface of a
bacterial cell. Similar to C1s, MASP2 is responsible for the activation of C4 and C2, which leads to the generation of the same C3 convertase (C4bC2a) as in the classical pathway. MASP1 is able to cleave C3 directly.
Describe activation of the alternative complement pathway.
The alternative pathway is initiated by the
low-grade activation of C3 by hydrolysed C3 (C3(H2O)) and activated factor B (Bb). The activated C3* binds factor B (B), which is
then cleaved into Bb by factor D (D) to form the alternative pathway C3 convertase, C3*Bb
Describe the central reaction of the complement activation cascade.
circulating C3 binds to a C3 convertase and is cleaved to produce C3a and C3b
What are the serine proteases that cleave C3?
C2a and Bb
Describe the amplification loop.
cleave many molecules of C3 to C3b, which bind covalently around the site of complement activation.
Can C3b amplify in the fluid phase?
What is the function of the C3b/C3 convertase complex?
cleaves C5 to C5b and C5a
What is the function of C5b?
recruits and binds C6, C7, C8, and multiple (or no) copies of C9
What is the function of the membrane attack complex? Describe the membrane channel
increase in cytosolic calcium, and fluctuations in intracellular potassium and sodium (heavy Na/K ATPase activity)
osmotic lysis or induction of apoptosis (intrinsic)
high phosphate and phospholipid content (ion channel)
What is the role of DAF or CD55? Where is it localized?
favors C3 convertase dissoication and inhibits C3 convertase assembly; weak cofactor for I lysis of c3b
membrane of most cells
What is the role of MCP or CD46? Where is it localized?
strong cofactor for I lysis of c3b; inhibits C3 convertase assembly
What is the role of complement receptor 1? Where is it localized?
strong co-factor for I lysis of c3b; promotes convertase dissociation and inhibits assembly
surface of myeloid and erythroid derived cells
What is the role of complement factor H?
Where is it localized?
strong co-factor for I lysis of c3b; inhibits B, C2, C3, C5 binding to c3b
plasma and ECF
What is the role of C1 esterase inhibitor? Where is it localized?
uncompetitive inhibitor of C1s, C1r, MASPs, and D; dissociates C1, MBP/MASP
plasma and ECF
What is the role of C4 binding protein? Where is it localized?
competitive inhibitor of C2 binding c4b and prevent B binding c3b
What is the role of CD59 or MIRL? Where is it localized?
inhibits insertion of C5b678; favors extrusion of the complex and reduces c9 binding
membrane of all cells (GPI-anchored)
What is the role of S protein? Where is it localized?
inhibits insertion of C5b6789
What determines self v. non-self in the classical pathway? lectin? alternative?
antibody specificity; high mannose and low sialic acid; high ROH/R3N and low sialic acid
Describe hereditary angineurotic edema
deficiency of C1 esterase inhibitor; lips are swollen and larynx is prone to suffocation
Describe paroxsymal nocturnal hemoglobinuria
blood and iron in the urine (due to hemolysis during the night); sleeping decreases pH by about 0.1-0.2
More severe disease with double functional knockout of DAF and MIRL by lack of GPI synthesis
can be supplemented by protein S, beta 1 h and others
Which complement molecule is the most abundant and most critical?
What are good activating surfaces?
Bacteria cell walls, protists, and other foreign pathogen
Which immunoglobulins activate the complement system?
IgG1, IgG3, and IgM
T/F: Complement proteins do not like acid?
What is C3*?
spontaneous hydrolysis of the thioester in C3
How does c3b* bind to the surface of pathogens?
the fluid phase convertase generated by spontaneous thioester hydrolysis hydrolyzes 3 to a metastable 3b that can bind to activating surfaces
The thioester bond in metastable C3b has been estimated to be 10(10) times more reactive than that in native C3 and mediates attachment of C3b to biological particles.
How do complement proteins affect leukocytes?
Inhibits migration away from the site of infection and reduces proteolysis to increase cytokine production
locomotion and chemokinesis
generation of lysoenzymes
What type of cells are granulated?
neutrophils, basophils, eosinophils, macrophages, monocytes, and T killer cells
What is the effect of complement proteins on granulated cells?
What is the role of factor I?
T/F: S protein is a soluble version of CD59?
Which pairs of complement molecules are important in inflammation by their recruitment (chemotaxis) of leukocytes as well as chemokinesis?
C3a and C5a
What are professional antigen presenting cells?
B cells, dendritic cells, and macrophages