Exam 3 Bold Words Flashcards
guanine-nucleotide exchange factors (GEFs)
-phosphorylated by Syk
-catalyze the exchange of guanine nucleotides on guanine nucleotide binding proteins
germinal center
-formed by b-cells that have migrated to a lymph follicle
-affinity maturation or become memory cells
inherited immunodefieciency
primary immunodeficiency
a disorder that occurs because some part of the immune system is missing or defective due to genetic disorders
acquired immunodeficiency
secondary immunodeficiency
a disorder that occurs due to non-inherited factors such as malnutrition, age, infection, disease, drugs, or toxins
combined immunodeficiency
these disorders result from impaired b-cell and T-cell production or responses
severe immunodeficiency
result from mutations that block the development of immune cells
tolerable immunodeficiencies
result from mutations that have limited effects in a select number of cells
most common type of inherited immunodeficiency
B cell immunodeficiencies are (1st)
combined immunodeficiencies (2nd)
T-cell immunodeficiencies (3rd)
innate immunodeficiencies (4th)
mutations in RAG1 or RAG2 result in
Omenn Syndrome
Omenn syndrome
mutations in RAG1 or RAG2
patients lack both T and B cells
People with Omenn syndrome can develop
severe combined immunodeficiency (SCID)
mutations in the C5-C9 genes can result in
an impaired ability to generate the membrane attack complex (MAC)
in general, b-cells can be activated by
an antigen being recognized by an immunoglobulin on the b-cell signals a humoral response from the adaptive immune system
compared to t-cell activation, b-cell activation
has signaling events that drive a similar mechanism for activation, division, and differentiation
naive b-cells are activated by
-multiple immunoglobulins recognizing an antigen and clustering on the cell surface
-a costimulatory signal is needed for proper activation
what effect does clustering of immunoglobulins have?
-crosslinking or clustering initiates signaling events involved in activation
-activity of Ig alpha and beta enable immunoglobulins to relay signals to the cytoplasm
the b-cell coreceptor acts as
-the second key
-analogous to CD28 for the t-cell coreceptor
what three polypeptides make the b-cell coreceptor
Cr2, CD19, and CD81
the ITAMs on Ig alpha and beta are phosphorylated by
Blk, Lyn, and Fyn
ITAMS can serve as what
the binding site for signaling molecule
what is Syk and how is it activated
Syk is a kinase in b-cells that is similar to ZAP70 in t-cells and is activated through the phosphorylated ITAMs which initiates gene expression changes
how does Syk activate b-cells?
-activates PLCgamma which initiates two different pathways
-phosphorylates and activates GEFs
PLCgamma cleaves what into what
phosphatidylinositol bisphosphate into diacylglycerol and inositol triphosphate
what three transcription factors promote b-cell proliferation and differentiation
NFAT, NFkB, and AP-1
what are two fates of b-cells
-differentiation into plasma cells that produce soluble IgM
-migration to a germinal center for affinity maturation or memory cell
how do b-cells migrate to a lymphoid follice
chemotaxis from the secretion of CXCL13 (a chemokine) by follicular dendritic cells
what are the two responses for clonal expansion of activated b-cells
- t-independent
- t-dependent
t-independent (ti)
thymus-independent
t-dependent (td)
thymus-dependent
what b-cells can activate through ti
b-1 b cells and marginal-zone b cells
what is the difference between ti-1 and ti-2 antigens
-ti-1 antigens bind to an immunoglobulin and a pattern recognition receptor (TLR4) on the b-cell surface
-ti-2 antigens are formed by repetitive unit (LPS) and cause clustering of immunoglobulin receptors
what b-cells are activated through td response
b-2 b-cells
td antigens
are recognized by the b-cell receptor and MHCII internalizes and processes them before they can be recognized by a t-cell receptor for the same antigen
what other signals are needed from a helper t-cell for activation of a td antigen-recognizing b cell
-cytokines such as IL-4
-CD40 ligand on the t-cell interacting with CD40 on the b-cell
what is CD40
the second key, b-cell coreceptor
what is the CD40 ligand
on the t-cell and binds to the CD40 molecule on the b-cell
how d t and b cells become a conjugate pair
-expression of ICAM-1 is induced on the b-cell by binding of CD40 to its ligand
-ICAM-1 binds tightly to LFA-1 on the t-cell
where does b-cell activation occur
secondary lymphoid tissue in the t-cell zone
what are the two fates of conjugate pairs
- migration to the medulla where b-cell differentiate into plasma cells
- migration to the medullary cord then the lymphoid follicles for clonal expansion into centrocytes
what is the primary focus
where the conjugate pairs are in the medullary cords and b and t cells can undergo clonal expansion
what is the secondary focus
where conjugate pairs are in the lymphoid follicle and follicular dendritic cells can provide signals for b-cell activation and proliferation
define aid
activation-induced cytidine deaminase
-in the secondary focus
-begins to be expressed when lymphoid tissues swell from cells dividing in the germinal center
-activates somatic hypermutation and isotype switching
how is immunoglobulin affinity maturation driven?
somatic hypermutation occurs within the germinal centers and is driven by the activity of AID through cytosine-to-uracil transitions which affects the binding of immunoglobulins on the b cell
how does the binding affinity of immunoglobulins occur
deamination of cytosine bases and subsequent DNA repair mechanisms change the original cytosine base to another base
where is the activity of AID
it is random toward cytosine bases in the variable regions of the immunoglobulin genes so there is either a positive or negative effect on the affinity of immunoglobulins for their antigens
what cells in the germinal center can present antigens to centrocytes and what does this do
-t-cells, follicular dendritic cells, and macrophages
-promotes additional round of positive and negative b-cell selection after somatic recombination has occurred
how does positive selection occur in germinal centers
-follicular dendritic cells present antigens to the immunoglobulins of centrocytes
-BAFF survival signals are gained by b-cells with a high enough affinity
-the bound antigen from the follicular dendritic cell is processed and present to helper t-cells
-helper t-cells provide survival signals to b-cells and express BcI-XL to prevent apoptosis
how is apoptosis of a b-cell in a germinal center with an altered immunoglobulin prevented
binding to both the follicular dendritic cell and helper t-cell
what do b-cells that are bound to follicular dendritic cells and helper t-cells in the germinal center differentiate into
plasma cells or memory cells
what happens if the altered immunoglobulin recognizes self-antigens
negative selection to remove or inactive the b-cell to prevent autoimmune disease
how is isotype switching driven and where does it occur
-occurs in the germinal center of the follicle
-cytosine deamination in the switch region of the immunoglobulin heavy chain loci
why is single-stranded DNA required for AID activity
AID can only act on DNA regions that are actively undergoing transcription or replication
what cytokines from helper t-cells can promote isotype switching
IL-4, IL-5, and TGF-beta
-they direct transcription at certain switch regions so that AID can target specific cytosines for proper isotype switching
what are some major immunoglobulin functions for fighting pathogen infection
-neutralization
-protection of internal tissues
-activation of innate immune cells
-complement activation
-clearance of small immune complexes
what do neutralizing antibodies do and why are they important
-they can prevent pathogens from interacting with target cells by interacting with the toxins and cell-surface molecules on pathogens
-this prevents toxin action and blocks pathogen entry into cells
-important for viruses
how are the isotypes of b-cells determined
by the Fc region for the constant region of the heavy chains
what do Fc receptors do
Fc receptors on innate immune cells bind to immunoglobulins and enhance the function of the cells
FcgammaRI
receptor on neutrophils that allow phagocytic cells to bind to the Fc portion of an immunoglobulin
how are pathogens tagged for removal by phagocytic cells
Fc receptors (FcgammaRI) that recognize IgG are expressed by macrophages and neutrophils that have opsonized a microbial surface and the receptor binds to the Fc portion of an immunoglobulin
what are examples of granulocytes
mast cells, basophils, and eosinophils
what do granulocytes do
expel pathogens from the body by activating inflammatory responses and muscle contraction for sneezing, coughing, etc.
inflammatory mediators
-histamine
-typically IgE
-secreted by activated granulocytes
-trigger expulsion mechanisms
what response do granulocytes work with
humoral adaptive immune response
how are histamines released
degranulation of mast cells caused by cross linking
what receptor does IgE tightly associate with
FcepsilonRI
how many different IgE immunoglobulins can a single granulocyte bind to
many different IgE immunoglobulins because there are multiple FcepsilonRI receptors on a granulocyte
why are natural killer cells important
they play an important role in the recognition of intracellular infection
antibody-dependent cell-mediated cytotoxicity
how nk cells target cells they bind are their FcgammaRIII receptor has coated them in IgG
how is the adaptive immune system able to recognize a wide variety of pathogens
-the diversity of t and b-cell receptors
-clonal selection of lymphocytes allows them to target and clear an infection
-memory cells from the primary immune response remember the specific pathogen
how long does it take the primary response to resolve infections
up to 14 days
-b-cell activation must be activated
-immunoglobulin isotypes are limited
how long does the secondary immune response take
3-4 days
-due to the differentiation and action of memory cells
what is the pattern of IgM and IgG during the primary response
IgM: increases around 11 days, reaches a peak at 14 days, then decreases
IgG: begins to increase around 14 days, reaches a peak at 21 days that is higher than IgM, then decreases
what is the pattern of IgM and IgG during the secondary response
IgM: increases around 4 days and has returned to basal levels before 10 days with a very small peak
IgG: increases around 3-4 days with IgM and reaches its peak around 14 days, then begins to slightly decreases, intensity of peak is the highest
what do memory cells that were produced from the primary immune response do
-respond quickly to a second exposure
-produce immunoglobulins that have undergone somatic hypermutation and isotype switching
-monitor for antigens in various tissues
what is the role of long-lived memory cells
trigger the rapid adaptive immune response upon exposure to their recognized pathogen
how are memory t-cells different from naïve t-cells?
-different cell-surface molecules are expresses
-populate different locations
-activated by different antigen presenting cells
what are the four subpopulations of memory t-cells produced during a primary adaptive immune response
-t memory stem cells (tscm)
-central memory t cells (tcm)
-effector memory t cells (tem)
-resident memory t cells (trm)
what can tscm’s differentiated into
tcm and tem
where are tscm’s found
circulatory and peripheral tissues like the lymph node
what is special about tscm’s
they have the potential for high survival, self-renewal, and multipotency for other memory t cells
where can tcm’s be found
circulatory but mostly lymphatic systems
what does tcm’s expression of IL-2 do
allows them to activate and differentiation into effector cells after exposure to specific antigen
where are tem’s found
secondary lymphoid tissues and circulatory and lymphatic systems
what does secretion of IFNgamma and TNFalpha do for tem’s
allows them to quickly activate and differentiation into effect t cells in peripheral tissues without the need to migrate through secondary lymphoid tissues
where are trm’s found
they reside within a peripheral tissue and do not leave so they can offer protection against recurring infection
what cell-surface markers are used to differentiate naïve and memory t cells
-chemokine receptor CCR7
-L-selectin (CD62L)
-CD103
what do activated b-cells within germinal centers produced
effector plasma cells responsible for secreting high-affinity, isotype-switched immunoglobulins
where do memory b-cells localize
the spleen
what does IgG produced by a reactivated memory b-cell do
-inhibits naïve b-cells from undergoing activation
-opsonizes the pathogen
variolation
-used the variola virus (smallpox)
-developed by edward jenner
-used pustule fluid
-worked as well as vaccination but caused smallpox in 1%
vaccination
-used the vaccinia virus (cowpox)
-cross protects against small pox
-worked as well as variolation but was less risky
the covid-19 vaccines developed by Pfizer/BioNTech and Moderna are
mRNA vaccines
how were covid vaccines able to developed, tested, and produced within 11 months
the coronaviruses that caused SARS in 2002-2004 and COVID-19 in 2020 were very similar so research was already being conducted
do vaccines cause autism
no, the 1998 study by Andrew Wakefield published in the Lancet that linked the MMR vaccine to autism faked all of its data and was eventually redacted (I wrote like two whole pages in an essay about the anti-vaccine movement about this study and the impact it has had)
what is the strategy behind vaccines
inducing a primary immune response that promotes the activation of the exact lymphocytes needed to combat the actual pathogen
what is the goal of vaccination
production of memory b and t cells
why does vaccination not provide absolute protection
“microbes can always find a way to get around your defenses” - dr. franklund
what are inactivated vaccines
killed or inactivated pathogens that are still antigenic but the virus can no longer replicate, which makes them ‘safer’
what are live attenuated vaccines
-utilize pathogens that have lost their ability to cause disease but are still alive
-the pathogen lives inside the host and allows the vaccine to mimic an infection
-provides IgA protection but can still mutate which is bad
is one dose enough for an inactivated vaccine to provide proper protection
no, booster doses are often required in order for an immune response that provides a high enough level of protection to be elicited
is one dose enough for a live attenuated vaccine to provide proper protection
yes, the vaccine closely mimics an infection so a robust immune response is produced with one dose
what are toxoid vaccines
vaccines that neutralize toxin products expressed by pathogens via immunoglobulin production
why can toxins for toxoid vaccines not be injected in their natural form
as much as 1 ng will kill you
how does a toxin become a toxoid
inactivation by formalin or heat treatment so they can be used in a toxoid vaccine
what are subunit vaccines
vaccines that raise a primary immune response to protect against pathogen adhesion molecules and prevent their entry into target cells
what are conjugate vaccines
multivalent vaccines that join a weak antigen (carbohydrate/polysaccharide coat) to a strong antigen (protein/toxoid) to produce multiple epitopes
what type of response is created by conjugate vaccines in adults
a t-independent response that produces opsonizing antibodies
what are recombinant vector vaccines
a vector (harmless bacteria or attenuated virus) has a plasmid for a pathogen antigen inserted and begins to express the antigen which leads to an adaptive immune response to the pathogenic antigen
what are dna vaccines
vaccine is placed directly into the host where is it picked up and incorporated into their genomic DNA, a vector is not used
what are messenger rna (mrna) vaccines
an mrna encoding an antigen target is delivered to a target cell which uptakes the mrna and translates the antigen to induce an adaptive immune response
what does a vaccine need to do to be effective
-promote clonal selection of lymphocytes that will be protective against a pathogen
-ensure that these lymphocytes receive a proper costimulatory signal
why is the induction of an inflammatory response good for a vaccine
it is needed in order to active expression of the costimulatory signal B7 (the 2nd key) on dendritic cells which is necessary for activation of naïve t cells
what is an adjuvant
an additive (ex-metals) to a vaccine that induces inflammation to strength the immune response
questions that must be addressed in developing a vaccine
-can the antigen revert to being pathogenic (saben polio vaccine)?
-can the antigen induce toxicity (cross reactivity)?
-are the adjuvant components safe in humans?
-was the vaccine developed in an organism that may induce an allergic response
what are modes of delivery for vaccines
-most are injected intramuscularly
-some can be inhaled (flumist)
-live attenuated rotavirus vaccines is given orally
what is the mucosa
-mucous membrane
-thin sheet of tissue that secretes mucous and lines body structures in respiratory, GI, and genitourinary tracts
-important front line for immune system to monitor for pathogens
what does the systemic immune response do (general)
innate and adaptive responses the protect most of the body produce an inflammatory response
what does the mucosal immune response do (general)
maintain mucosal barrier to prevent contact between environments
what is mucus
thick viscous fluid covering mucosae that lubricates and protects mucosal surface
how does mucus prevent microbial colonization
proteoglycans and glycoproteins work with peptides and enzymes to inhibit pathogens
what are mucins
family of glycoproteins secreted by epithelial cells that allows for o-linked glycosylation (ser and thr) that increases the molecular weight and viscosity to inhibit the movement of pathogens
what does mucosa-associated lymphoid tissue (malt) do
promote antigen delivery to circulating lymphocytes to ensure protection of mucosal barriers
what is the function of malt’s
centralize activation of an adaptive immune response at mucosal surfaces
where are malt’s located
beneath epithelial cells, sometimes referred to as inductive compartment
what are different types of malts
galt
balt
calt
nalt
what are galt’s
-gut-associated lymphoid tissue
-activated lymphocytes and macrophages residing in connective tissue below mucosal epithelia
how is the lamina propria important to galt’s
the connective tissue that is also referred to as effector compartment and contains immune effector cells such as b, t, macro, and dendritics
what are peyer’s patches
aggregated lymphoid nodules that are aggregations of galt in small intestine
what do isolated lymphoid follicles of the gi tract contain
b cells
how does the gut microbiota help us
-compete with pathogens for space and nutrients
-aid in digestion and produce important vitamins
-produce metabolic products and antimicrobial agents
-may be responsible for development of mucosal immunity
-act as a sparing partner to keep the immune system stimulated
how does the microbiota help the lamina propria
help develop TH17 helper t cells, which are a major cell in the lamina propria
how are interactions between the microbiota and epithelial cells limited
-mucus, mucins, IgA, and antimicrobial peptides
-tight junctions between cells that prevent migration of microorganisms
what are danger associated molecular patterns (damps)
-raw nucleic acids
-heat shock proteins
-cytokines
-plasma membrane proteins (sign of cell lysis)
what are microfold cells (m cells)
epithelial cells that ‘quietly’ deliver antigens to galt via transcytosis
how do m cells do transcytosis
the luminal side of the m cell binds the microorganism, engulfs it, and transports it to the apical side facing galt
what is the intraepithelial pocket
formed by extensive folding and provides location for antigen delivery
how do dendritic cells deliver antigens to malt in the lamina propria
projections are extended through the barrier and bind to pathogens in the gut lumen, then take them up and process them before they are moved to malt or mesenteric lymph node for antigen presentation
how do mucosal epithelial cells utilize tlr’s
toll-like receptors recognize pathogens and activate NFkB, produce the inflammatory cytokines IL-1 and IL-6, produce antimicrobial peptides and chemokines
what is nod
a family of intracellular proteins that bind bacterial cells wall components and activates a signaling cascade
NOD1 and NOD2 are present where
mucosal epithelial cells
what innate immune cells are present at mucosal surfaces
-intestinal macrophages
-gut dendritic cells
-innate lymphoid cells
what do intestinal macrophages do
-remove microorganisms in the lamina propria via phagocytosis
-prevent damage to the mucosal surface due to their lack of inflammatory cytokines such as TNFalpha, IL-1, and IL-6
how is oral tolerance provided
by gut dendritic cells that take up digested food and activate Treg cells that recognize commensal and foreign pathogens
why is oral tolerance important
foreign antigens encountered during digestion pose no disease threat and we need to be able to eat
what are some innate lymphoid cells
ILC1, ILC2, ILC3
what does ILC1 do
activate macrophages and dendritic cells by secreting IFNgamma
what does ILC2 do
secrete cytokines like IL-5 to promote activation of granulocytes and respond to proteins produced by helminth infection
what does ILC3 do
secrete cytokines IL-22 (epithelial cell antimicrobial peptide secretion) and IL-17 (neutrophil activation)
why do naïve b and t cells leave malt
CCL19 and CCL2 that bind CCR7 receptor are secreted by secondary lymphoid tissues and if they do not find antigen they migrate to different lymphoid tissues
what makes up the heterogenous t cell population
-alpha:beta or gamma:delta
-CD4 or CD8
where are plasma cells and what immunoglobulin do they secrete
80% are in mucosal tissue and secrete mostly IgA but can secrete IgM, IgG, and IgE
what two immunoglobulins neutralize pathogens at mucosal surface and why
IgA and IgM, they have multiple binding sites
what is the difference between IgA and IgM
IgM: pentameric, 10 binding regions, able to activate complement through classical pathway
IgA: dimeric, 4 binding regions, serves as neutralizing antibody, cannot activate complement
what is different in the IgA subclasses
the hinge region connecting Fab and Fc region of the heavy chain
what is the difference between the IgA subclasses IgA1 and IgA2
IgA1: longer and more flexible hinge region is able to bind multiple epitopes on a single pathogen
IgA2: shorter and less flexible hinge region is more resistant to protease cleavage from pathogens
what are some of the mucosal infections people with a selective IgA deficiency are susceptible to
-sinus infections
-respiratory infections
-GI infections
-chronic diarrhea
how would you describe an IgA defficiency
“hypersensitive and hypersusceptible” - dr. franklund
how do effector t-cells fight helminth infection
increase helminth shedding when CD4 cells activated are Tfh and Th2 cells that activate IgE producing plasma cells and cytokines
what are some tactics that pathogens use to evase the immune system
-genetic variation leading to changes in surface molecules
-mimicking host molecules
-hiding in host cells
-altering the host immune response by producing substances such as toxins or superantigens
-competing against the host to survive and multiple despite the innate and adaptive immune responses
how pathogens evade the immune system through genetic variation
because the immune system recognizes through receptors or antibodies, pathogens can mutate to change their surface to avoid detection by the immune system
what antigen is in LPS
o-antigen
what antigen is in matrix
m-antigen
what antigen is in capsule
k-antigen
what antigen is in flagella
h-antigen
what are bacterial serotypes
different surface antigens in a bacteria
what is hemagglutinin
viral fusion with target cells so they can get in
what is neuraminidase
release of mature viral particles from the host cells so they can get out
what is antigenic drift
genetic changes that can arise through replication of viral genomes by error-prone nucleic acid polymerases (variant strains)
what does antigenic drift lead to
changes in the surface molecules of the virus that the immune system cannot recognize
what is antigenic shift
closely related variants infect the same host cell and mix their genetic components during replication and assembly to create new viral particles with characteristics from both strains
what can antigenic shift cause
pandemics because the new virus has not been encountered before
what are zoonotic pathogens
pathogens from animals
what are three different mechanisms for genetic variation in pathogens
- having multiple varied copies of a gene that contain their own on/off switch
- having one expression locus with many silent gene copies that be switched into locus via gene rearrangement when necessary
- having a highly variable region in a gene product that can change when necessary
how does neisseria spp. exhibit antigenic variation
- uses multiple gene copies of Opa outer membrane protein
- express variant of the pilin gene
- vary sugars at ends of lipooligosaccharide molecules in their outer membranes
what is viral latency
viruses are still alive but not actively replicating so they can invade the immune system
what are extracellular bacteria targeted by
phagocytosis, opsonization, and neutralization via immunoglobulins
how do intracellular pathogenic bacteria avoid destruction
-survive within the cytosol of the phagocyte and escape the phagosome
-prevent the formation of the phagolysosome
-survive in the phagolysosome without being digested by the phagocyte
how is the phagosome escaped
use a pore-forming toxin to punch holes in the phagosome membrane
how is the fusion of phagosome-lysosome blocked
target proteins involved in membrane trafficking and fusion
how do pathogens survive in the phagolysosome
polysaccharide capsule inhibits reactive oxygen species produced in the lysosome
what do bacterial toxins do
alter normal immune system behavior or cellular activity
what are the two groups of toxins
endotoxins (present as a component of the pathogen) and exotoxins (secreted by the pathogen)
how do extracellular pathogens disrupt phagocytosis
inhibit the actin cytoskeleton needed for phagocytosis
how is cytokine signaling disrupted
target the expression of cytokines and block the activation of NFkB
how does disruption of toll-like receptors affect detection
pathogens can persist if tlr’s cannot signal detection
how is the complement system disrupted
-preventing complement fixation
-precent membrane-attack complex formation
how is the adaptive immune system disrupted
-subverting mhc1 presentation
-blocking lymphocyte activation or lymphocyte effector mechanisms
-degrading IgA at mucosal surfaces using an enzyme
tolerable immunodeficiencies
result from mutations that have limited effects in a select number of cells
why is a b-cell immunodeficiency most common
b-cell immunodeficiencies can be tolerable but t-cell and innate cell immunodeficiencies usually cause severe morbidity
sever combined immunodeficiency
-scid
-susceptible to infection by many types of microbes
-lack both t and b cells
-results from impaired immune cell development
examples of acquired immunodeficiencies
-lack of vitamin a in people who are malnourished
-aids caused by hiv
how can the first defenses be targeted for increases susceptibility to infections
-defects in epithelial barriers and pathogen recognition receptors
-defects in peptides and enzymes that enhance pathogen-fighting activities
how can an immunodeficiency of the complement system arise
defects in virtually any component of the complement system can result in impaired responses to microbes
hereditary angioneurotic edema (hane)
-results from mutations in the c1 inhibitor (c1-inh) gene
-C1 is not inhibited by the C1 protease so C2 and C4 do not get cut
-there is too much C2a which is a vasodilator and causes edema
neutropenia
result of mutations that affect neutrophil development which creates a susceptibility to microbial infections
how can phagocyte function be impared
lack of specific immune cells or mutations that affect phagocytic pathways
ex) defects in NADH oxidase or proteins related to the oxidative burst
leukocyte adhesion deficiency (lad)
-due to mutations in the beta-2 integrin that is shared by the LFA-1, CR3, and CR4 adhesion proteins
-loss of LFA-1 impairs innate cell migration to sites of infection
-loss of CR3 and CR4 results in an inability to efficiently recognize C3b on pathogens
-patients are susceptible to recurrent acterial infections
chediak-higashi syndrome
-autosomal recessive mutation in LYST gene
-LYST protein is normally responsible for formation of phagolysosome
-susceptible to recurring gram+ bacterial infections
chronic granulomatous disease
-mutations in genes responsible for the function of NADPH oxidase
-nadph oxidase activity results in production of reactive oxygen species and the respiratory burst
-inefficient killing of microbes result in chronic inflammation and formation of granulomas
-susceptible to recurrent bacterial and fungal infections
classical nk cell deficiency
-results from impaired production of nk cells
-caused by rare mutations in the transcription factor GATA3 or the dna replication protein MCM3
functional nk cell deficiency
-results from impaired function of nk cells
-caused by rare mutation in the FCyR CD16 gene that is responsible for initiating antibody-dependent cell-mediated cytotoxicity (adcc)
adenosine deaminase (ada) deficiency
-build up of dATP in developing lymphocytes inhibits cells from completing cell division
how are scid patients treated
-diagnosis it pre or perinatally so treatment can begin after birth
-bone marrow transplant to restore normal lymphocyte production
-transfer of antibodies from healthy individuals
why are t-cell immunodeficiencies so severe
t-cells have many function including initiation of immune responses and killing infected cells which results in susceptibility to bacterial, fungal, and viral infections
JAK3 deficiency
-the y-common chain of cytokine receptors involved in t-cell development and maturation is mutated
-JAK3 signals downstream of the y-common chain so when mutated it cannot signal
purine nucleotide phosphorylase (pnp) deficiency
-similar to ada deficiency but developing t-cells are mainly affected
-clonal expansion is shut down because dGTP builds up and DNA synthesis is shut down
DiGeorge Syndrome
-chromosomal translocation resulting in multiple defects in organ development
-lack of a thymus so there is reduced t-cells and susceptibility to many microbial infections
bare lymphocyte syndrome (bls)
-loss of mhc proteins on the cell surface results in an inability of t-cells to become activated
defects in tcr signaling pathways
-mutations in CD3 signaling proteins or in ZAP70 can result in both reduced t-cell production and impair t-cell activation
-can also be caused by immunosuppressive drugs that block t-cell signaling pathways
x-linked agammaglobulinemia
-most common b-cell scid
-due to mutations in Bruton’s tyrosine kinase (BTK)
hyper IgM syndrome
defects in isotype switching signals or enzymes results in overproduction of IgM isotype antibodies and inefficient switch t other isotypes
Selective IgA deficiency
-defects in transport of IgA from basal to apical mucosal epithelia
-results in poor neutralization of microbiota and recurrent opportunistic infections
-can also result in asthma due to poor clearance of environmental antigens or autoimmunity
human immunodeficiency virus
retrovirus with an RNA genome that is packaged while proteins needed for reverse transcription and replication
reverse transcriptase
converts RNA to DNA
integrase
integrate cDNA into host genome
HIV protease
cleaves polypeptides into functional proteins
gp120 and gp41
binds to CD4 and a co-receptor (either CCR5 or CXCR4)
know stuff about HIV and AIDS
there were a lot of slides about them
hypersensitivity reaction
stimulation of an immune response to a harmless foreign material
allergies
one of the most common type of hypersensitivity reactions
-type 1 hypersensitivity
allergens
-recognized by the immune system and inflammatory mediators are released
-typically small peptides, proteins, or drugs
type 1 hypersensitivity
mast cells, eosinophils, and basophils respond to a foreign molecule capable of binding to IgE associated with these granulocytes
type 2 hypersensitivity
IgG immunoglobulins which recognize cell-surface molecules target cells containing these molecules via the complement pathway or antibody-dependent cell-mediated cytotoxicity
type 3 hypersensitivity
caused by the action of IgG recognizing soluble antigens and forming immune complexes which results in unnecessary activation of complement and activation of phagocytic cells
serum sickness
example of type 3 hypersensitivity
type 4 hypersensitivity
caused by the delayed activation of t cells by a foreign, harmless antigen
delayed-type hypersensitivity
-when the type 4 hypersensitivity response is induced
-dictated by the type of t cells that are activated
examples of inflammatory mediators
histamine, leukotrienes, prostaglandins, heparin
what is the hygiene hypothesis
“kids don’t eat enough dirt”
increases in allergies in developed countries may be due to lack of exposure to microorganisms
how do granulocytes mediate hypersensitivity
granulocytes have Fc receptors specific for IgE (Fcepsilon) that allergens bind to
how do mast cells contribute to type 1 hypersensitivity
mast cells in conjugation with IgE release inflammatory mediators from cytosolic granules when they recognize pathogens which causes allergic responses from rhinitis to anaphylaxis
how are basophils involved in type 1 hypersensitivity
basophil degranulation is activated similarly to mast cell degranulation when antigens are recognized via associated IgE
how are eosinophils involved in type 1 hypersensitivity
IgE signaling causes eosinophils to secrete proteins such as inflammatory mediators (histamine and prostaglandins) and toxic molecules
what are routes of entry for an allergen and how severe are they
less severe: skin contact, inhalation
more severe: ingestion, injection
how does exposure to an allergen lead to an allergic reaction
-an individual is sensitized by first exposure to the antigen which elicited the primary adaptive immune response
-allergen-specific t and b cells and IgE that binds to granulocytes are produced
-second exposure to the allergen causes an allergic reaction
wheal-and-flare reaction
a small amount of allergen is injected and results in a raised skin lesion containing fluid (wheal) surrounded by a red, itchy area (flare)
urticaria
-skin reaction
-hives
-itchy, red welts on the skin
what is anaphylaxis
a widespread activation of blood-vessel-associated mast cells in the body caused by allergens in the blood stream that results in body-wide vasodilation
atopic
individuals with an increased predisposition to type 1 hypersensitivity and express more IgE that are capable or recognizing innocuous allergens
what are some treatments for allergy symptoms
-corticosteroids used in topical creams and oral/inhaled forms to suppress the action of inflammatory mediators
-immunotherapy with oral or injection administration of allergens to desensitize the individual
what are examples of IgM and IgG activity in type 2 hypersensitivity reactions
-opsonization in phagocytosis
-activation of complement on recognized cells
-activation of antibody-dependent cell-mediated cytotoxicity
antibody-dependent cell-mediated cytotoxicity
using the FcgammaRIII receptor, NK cells recognized bound IgG and target the cell by releasing cytotoxic molecules and inducing apoptosis
what is the result in a type 2 hypersensitivity reaction
-destruction of the cell through phagocytosis
-lysis through action of MAC
-destruction by NK cells
how can transfusion of incompatible blood produce a type 2 hypersensitivity reaction
immunoglobulins to certain blood type glycolipid antigens can mark blood cells bearing those glycolipids as ‘foreign’
type o blood
have H antigen glycolipids and do not have glycosyltransferases that can modify H antigen
type a blood
express glycosyltransferase that adds the carbohydrate n-acetylgalactosamine to h antigen
type b blood
express glycosyltransferase that adds the carbohydrate galactose the h antigen lipid
type ab blood
express both glycotransferases and can make both a and b antigen glycolipids
what rhesus factor is most important
Rh D antigen
what does it mean to have a positive blood type
the individual is positive for the Rh D antigen
hemolytic disease of the newborn
-a type 2 reaction that occurs during pregnancy when an Rhneg mother conceives an Rhpos fetus after giving birth to an Rhpos child
-Rh-specific IgG production results in destruction of fetal RBCs resulting in severe anemia or death of the developing fetus
crossmatching
checks for harmful interactions between a potential donor and recipient of blood, tissue, or an organ
what occurs in a type 3 hypersensitivity reaction
IgM and IgG recognize soluble antigens and prompt the formation of immune complexes and inefficient clearance results in abnormal activation of inflammatory responses and cells that attempt to clear the immune complexes
what factors influence if immune complexes can drive a type 3 hypersensitivity reaction
-the affinity of a particular antigen to a specific location or tissue
-disruption of normal phagocytosis
-the chemical nature of the antigen which plays a role in how efficient phagocytic cells are at engulfing the antigen
serum sickness
type 3 hypersensitivity reaction
arthus reaction
type 3 hypersensitivity reaction that occurs when large amounts of antigen are deposited and immune complexes form
what are the phases of type 4 hypersensitivity reactions
sensitization phase and effector phase
what is required for a type 4 hypersensitivity reaction
antigen-presenting cells to present to t cells
what happens in the sensitization phase of a type 4 hypersensitivity reaction
APCs present antigen to T cells via mhc molecules to activate the t cell bearing the receptor that can recognize the mhc antigen complex
what happens in the effector phase of type 4 hypersensitivity reaction
-a subsequent exposure to the sensitized t cell drives differentiation of the t cell into an effector t cell
-the t cell activated is usually a TH1 helper t cell, which secretes IFN-y and CXCL8, activating and recruiting macrophages
how are type 4 hypersensitivity reactions induced
intracellular bacteria, viruses, fungi, and chemicals
