Immunology ✔ Flashcards
how does vaccination work?
Exposure to a pathogen/antigens stimulates an acquired immune response. –> Immunologic memory is developed by stimulation of T and B lymphocytes specific for the epitopes on this pathogen. –>
Some of these cells become long living memory cells, capable of responding to the viable pathogen upon encounter.
what is the natural & normal development of effector lymphocytes?
primary lymphoid organs make some naïve lymphocytes which wait for an antigen to be presented by an APC. This leads to clonal expansion of the lymphocytes, and some are remembered as effector lymphocytes
what is an antigen presenting cell?
a cell that can present peptides to T lymphocytes to initiate an acquired immune response
what types of cells are antigen presenting cells?
macrophages
B lymphocyte
Langerhans cells
Dendritic cells
how do CD4 T cells work for immunity?
an antigen is presented by an APC to a CD4 T cell. This activates the CD4 T cells which produces cytokines. In the meantime, the CD4 T cells undergo clonal expansion… “helper T cells”
This expansion requires the cytokines and a specific antigen
what are helper T cells?
CD4 T cells. Because they ‘help’ other lymphocytes
how does the immune system work to provide protection with CD8 T cells?
an antigen is presented by APC to a CD8 T cell. The CD8 cell is then activated which releases cytokines and causes clonal expansion. At this point T helper cells (CD4) provide help to CD8 cells with cytokine GF. Some of these CD8 cells are then kept in reactive memory and some effectors kill the virus infected cells
what is the role of T helper cells with relation to CD8 T cells?
they help to illicit the clonal expansion and cytokine release with the provision of cytokine growth factor
what are the two types of activated CD8 T cells that provide immune protection?
- effectors: kill virus infected cells
- reactive memory cells: remember if the antigen presents again in future
how do B cells work in providing immunity?
specific antigen will activate an immediate cytokine response and the cytokines work with T -helper cells (CD4) to activate B cells for expansion and isotype switching. The effector cells of B cells are plasma cells that produce antibodies. Some B cells remain memory cells
what types of cells have remaining memory cells that will recognize if this same antigen comes up again?
- B cells
- CD8 T cells
which types of cytokines create a cell-mediated immune response?
Th1, type 1 cytokines: IL-2, IFN-gamma, TNF
which types of cytokines create a humoral response?
Th2, type 2 cytokines: IL4, IL5, IL6
what is the target for infectivity-neutralizing antibodies in influenza?
hemagglutinin is the receptor binding and membrane fusion glycoprotein of influenza virus
what is the main cell involved in TB immune response?
T- cell mediated
what antibody mediates primary immune response?
IgM
what antibody mediates secondary immune response?
IgG but some IgM is still present
what is the difference between immediate and memory immunity?
- memory immunity is more rapid and more aggressive because the memory cells have higher affinity to antigen and are more activated
- different pattern of expression of cell surface proteins
- memory t-cells are maintained for a long time without antigen by continual low level proliferation in response to cytokines
which cytokines are involved in memory cells proliferation without antigen?
IL2
IL7
IL15
what are the two subsets of memory T cells?
1) central memory T cells (TCM)
2) effector memory T cells (TEM)
the difference is the presence of CCR7 on endothelial cells and CD62L presence
what is the difference between central memory T cells and effector memory T cells in action?
central memory: migrate efficiently to peripheral LNs. Produce IL-2, no IFN, no perforin
effector memory: found in other sites from LNs (eg liver, lungs); little IL-2 but high IFN/perforin
what are the three phases of T cell immune response?
1) expansion
2) contraction
3) memory
what are the main parts to vaccine components?
1) live, attenuated
2) inactivated/component
3) adjuvant
what are some examples of live and attenuated vaccines?
yellow fever MMR typhoid TB (BCG) Polio
what are the advantages of live vaccines?
- Establishes infection,
- Often confers lifelong immunity after one dose (no boosters).
- Activates all phases of immune system. Can get humoral IgG and local IgA.
- Raises immune response to all protective antigens.
- More durable immunity; more cross-reactive.
what are the disadvantages of live vaccines?
- Possible reversion to virulence (recombination, mutation).
- Storage problems (cold chain)
- Safety issues
- Problem in immunodeficiency
what are some examples of inactivated vaccines?
- influenza
- cholera
- polio
- hepatitis A
- rabies
- DTaP
what are some advantages of inactivated vaccines?
- No mutation or reversion
- Can be used with immuno-deficient patients
- Can lead to elimination of wild type virus from the community
- Storage easier
- Lower cost
what are some disadvantages of inactivated vaccines?
- some components have poor immunogenicity
- may need multiple injections
- may require adjuvants
what is an adjuvant and give an example?
Adjuvant increases the immune response without altering its specificity.
A depot adjuvant acts by slowing the release of antigen. e.g. Alum
what is the method of action of DNA vaccines?
- a plasmid containing the gene of choice that will confer immunity to the pathogenic bits
- inserted into muscle cell (several copies)
- no replication of the plasmid
- expression of gene at cell surface so immune response generated
why don’t vaccinations work effectively in the elderly?
- immune senescence (inc. frequency of terminally differentiated effector memory T cells already exist with reduced production of recent thymic emigrants that are ‘naïve T-cells’
- nutrition (insufficient energy/vitamins & minerals)
what defines atopy?
production of specific IgE responses to common environmental antigens - a marker of sensitization ONLY and not disease
what type of hypersensitivity is in allergic disease?
type I
what is the difference between atopy and allergic disease?
atopy - sensitized
allergic disease - type I hypersensitivity reaction to allergens
what is the age of onset of most food allergies?
infancy
what is the age of onset for hayfever/asthma?
childhood
what sorts of allergies onset as adults?
- drug allergy
- bee allergy
- oral allergy syndrome
what are the clinical features of IgE allergic responses?
- Occurs within minutes or up to 2 hours after exposure
- symptoms: angioedema, urticaria, pruritus, rhinitis conjunctivitis, wheeze, diarrhoea vomiting and anaphylaxis.
- > 2 organ systems are usually involved.
how do we investigate allergic disease?
- skin prick tests
- Lab measurement of IgE
- component-resolve diagnostics
- challenge test
what is the ‘gold standard’ for diagnosing allergies?
- skin prick tests
- if positive, local wheal/flare response to allergen (>2mm)
what is a RAST test?
- specific IgE test
- Measure IgE in serum directed against a specific allergen (peanut, cat dander, egg etc)
- used to confirm dx of allergy, check prognosis
what are the indications for RAST testing?
- patients who can’t stop antihistamines (for skin prick)
- dermatographism
- extensive eczema
- history of anaphylaxis
- borderline skin prick test results
what is component resolved diagnostics for allergens?
- detect individual allergens within a protein against which the immune system makes IgE antibodies (eg peanut contains at least 5 major allergens)
- can allow the clinician to predict whether a patient will experience sx
how would we check if someone is having an acute allergic reaction?
- mast cell tryptase test
- product of mast cell granules which means when mast cells degranulate in allergic reaction the levels of serum tryptase increase
- peak at 1-2 hours; return to baseline by 6-12 hours
what is the gold standard test for food allergy diagnosis?
challenge tests (inc. volume of food are ingested in order to interpret which level leads to symptoms). Done under close medical supervision.
what defines anaphylaxis?
severe systemic allergic reaction involving respiratory difficulty and hypotension; usually involves skin or N&V
what are the 3 criteria required to diagnose anaphylaxis?
1) sudden onset/rapid progression symptoms
2) life threatening ABC issues
3) skin & mucosal changes
what are the mechanisms of anaphylaxis (+ examples)?
- IgE mediated mast degranulation (eg peanuts, penicillin, bee venom, latex)
- non IgE mediated mast cell degranulation (eg NSAIDs, IV contrast, opioids)
if we want to do a serum tryptase level to check for real anaphylaxis, when do we check?
-1 hour
-3 hour
-24 hours
Rise in tryptase is proportional to hypotension
what is the emergency management of anaphylaxis?
- IM adrenaline 500 mcg
- oxygen & fluids
- hydrocortisone 100mg IV
- (if skin rash) chlorpeniramine 10mg IV
- Follow up with referral to allergy clinic to investigate cause
- Give epipen
what are the appropriate investigations for food allergies?
- a positive SPT is useful to confirm but a negative skin prick test (SPT) excludes IgE mediated allergy
- the Gold standard for diagnosis of food allergy is a double blind oral food challenge.
what cells are involved in an innate immune response?
- phagocytes: macrophages & neutrophils
- NK cells
- dendritic (APC) cells
- complement
what cells are involved in adaptive immunity?
- CD4
- B cells
- CD8
what are causes of secondary immunodeficiency?
1) infection - HIV, measles, mycobacterium
2) biochemical - malnutrition, mineral deficiencies, renal impairment
3) malignancy - myeloma, leukemia, lymphoma
4) drugs - steroids, cytotoxic
how does the skin work as a constitutive barrier to infection?
1) tightly packed keratinized cells
2) physiological - low pH, low O2
3) sebaceous glands ( + lysozymes, ammonia…)
how do mucosal surfaces work as barrier to infection?
1) mucous as physical barrier and IgA secretion
2) cilia
3) commensal bacteria
what cells and soluble components are in the innate immune system?
cells: neutrophils, eosinophils, basophils, dendritic cells, NK cells, monocytes, macrophages
components: complement, APP (CRP/ESR), cytokines, chemokines
how do cells of the innate immune system recognize antigens at site of infection?
PRR: pattern recognition receptors like TLR which recognize pathogen-associated molecular patterns (PAMPs) generic motifs
how does the innate immune system combat infection?
- chemokines/cytokines
- PRR to activate and go to active CD8 T cells/ B cells
- phagocytic capacity for pathogens
how do Neutrophils, Eosinophils and Basophils/Mast cells work in the immune system?
- produced in bone marrow
- migrate rapidly to site of injury
- release enzymes, histamines, lipid mediators of inflammation from degranulation
where are monocytes & macrophages made? what do they do?
monocytes are produced in bone marrow and differentiate into macrophages in the tissues of the body. They are APCs to T cells.
list the macrophages for the following organs: Liver Kidney Bone Spleen Lung Neural Skin
Liver - Kupffer Kidney - Mesangial Bone - osteoclast Spleen - sinusoidal lining cell Lung - alveolar macrophage Neural - microglia Skin - Langerhans
what sort of infections are contracted when someone is phagocyte deficient?
- recurrent skin/mouth infections (Staph aureus, Candida, Aspergillus)
- mycobacterial infection
what is the condition where stem cells fail to differentiate along myeloid lineage and produce neutrophils?
“reticular dysgenesis”
- AR inheritance
- severe SCID
- mutation in mitochondrial energy metabolism enzyme AK2
what is reticular dysgenesis?
autosomal recessive severe SCID
- failure to produce neutrophils
what is Kostmann syndrome?
AR severe congenital neutropenia (a specific failure of neutrophil maturation)
*due to mutation in HAX1 associated protein
what is the syndrome where someone fails to mature neutrophils?
Kostmann syndrome - AR
or cyclic neutropenia - AD
what is cyclic neutropenia?
an AD inherited episodic neutropenia every 4-6 weeks. Due to mutation in neutrophil ELA2
what is leukocyte adhesion deficiency?
- a deficiency of CD18
- usually expressed on neutrophils, binds to ligand (ICAM-1) on endothelial cells and so regulates neutrophil adhesion/transmigration
- -> In Leukocyte adhesion deficiency the neutrophils lack these adhesion molecules and fail to exit from the bloodstream
how does leukocyte adhesion deficiency present?
characterized by
very high neutrophil counts in blood
absence of pus formation
what happens if somebody has a defect in complement production or antibody production?
decreased efficiency of opsonisation –> affects phagocyte function
what is chronic granulomatous disease?
- failure of oxidative killing mechanisms
- inability to generate oxygen free radicals
- impaired killing of intracellular micro-organisms
- excessive inflammation
- persistent neutrophil/macrophage accumulation
- granuloma formation
how does chronic granulomatous disease present?
- lymphadenopathy
- hepatosplenomegaly
how do we investigate chronic granulomatous disease?
- nitroblue tetrazolium (NBT) test
- dihydrohodamine (DHR) flow cytometry test
what is the important of IL12 and IFN?
IL12, IL12R, IFNg or IFNg R deficiency may cause susceptibility to mycobacterial infections
what conditions come from a failure of neutrophil differentiation? (3)
- reticular dysgenesis
- severe congenital neutropenia (Kostmann’s)
- cyclic neutropenia
what condition arises from failure to express leukocyte adhesion markers?
leukocyte adhesion deficiency
what part of innate immune system fails of there is an antibody or complement deficiency?
failure of opsonisation
what disease is characterized by a failure of oxidative killing?
chronic granulomatous disease
spot diagnosis: recurrent infections with high neutrophil count, no abscess formation
a) IFN gamma receptor def.
b) Leukocyte adhesion def.
c) Chronic Granulomatous Disease
d) Kostmann’s syndrome
b) leukocyte adhesion deficiency
spot diagnosis: recurrent infections with hepatosplenomegaly, abnormal DHR test
a) IFN gamma receptor def.
b) Leukocyte adhesion def.
c) Chronic Granulomatous Disease
d) Kostmann’s syndrome
c) chronic granulomatous disease
spot diagnosis: recurrent infections with no neutrophils on FBC
a) IFN gamma receptor def.
b) Leukocyte adhesion def.
c) Chronic Granulomatous Disease
d) Kostmann’s syndrome
Kostmann’s syndrome
spot diagnosis: infection with atypical mycobacteriums, normal FBC
a) IFN gamma receptor def.
b) Leukocyte adhesion def.
c) Chronic Granulomatous Disease
d) Kostmann’s syndrome
a) IFN gamma receptor deficiency
how do natural killer cells work in the immune system?
- have two receptors: one is inhibitory and one is activating
- a normal cell matches on both receptors –> no lysis
- a target cell does not match on the inhibitory receptor –> cytotoxicity, cytokine secretion, lysis
what sort of infections do we get if we have natural killer cell deficiencies?
viral infections - HSV, HPV, VZV, EBV, CMV
what is the treatment for NK cell deficiencies?
- prophylactic antiviral drugs
- cytokines to stimulate function
what are the two classifications of NK cell deficiencies?
- functional
- classical (absence of them)
what do dendritic cells do in the immune system? (NB- list multiple things!)
- Express receptors for cytokines and chemokines - to detect inflammation
- release cytokines
- Express PRRs – to detect pathogens
- Express Fc receptors for Ig - to detect immune complexes
- Capable of phagocytosis
- mature following phagocytosis by migrating, upregulating HLA, expressing costimulatory molecules
- Present processed antigen to T cells in lymph nodes to prime the adaptive immune response
what is complement?
> 20 tightly regulated proteins produced by the liver and present in the circulation as inactive molecules. If activated, enzymatically activate other proteins in biological cascade for amplified response
what are the 3 pathways of complement activation?
-classical (via C1, C2, C4)
-MBL (via C4, C2)
-alternative
All finish in final common pathway via C3 –> C5-C9 –> Membrane Attack Complex (MAC)
what other roles do complement fragments play in the immune response?
- increase vascular permeability
- increase cell trafficking to site of inflammation
- solubilize and clear immune complexes
- opsonisation of pathogens (phagocytosis)
- activate phagocytes
- promote mast cell/basophil degranulation
- punch holes in bacterial membranes
how does the classical pathway activate complement?
- formation of Ab-Ag immune complexes
- change in Ab shape –> binding site for complement C1
- binding of C1 –> activates C4/C2 –> activate C3 –> activates cascade
what’s the disadvantage of the classical pathway of complement activation?
dependent upon activation of acquired immune response
what happens if somebody has a defect in the early classical complement activation pathway?
- immune complexes fail to activate complement pathway
- increased infection susceptibility
- associated with SLE from deposition of immune complexes
how does the MBL system work to activate complement?
MBL: mannose binding lectin
- activated by direct binding of MBL to antigen surface carbohydrates
- directly stimulates classical pathway
- NOT dependent on acquired immune response
how does the alternative pathway work to activate complement pathway?
- bacterial cell wall fails to inactivate C3b (eg LPS on gram negative or teichoic acid of gram positive)
- so still activates C3 and goes through complement pathway
- NOT dependent on acquired immune response
what happens if somebody has a defect in the alternative complement pathway?
- inability to mobilize complement rapidly in response to bacterial infections
- recurrent infections with encapsulated bacteria (bacterial cell wall is able to inactivate C3b)
since all 3 pathways activate C3 in the complement pathway activation, what happens if there is a defect and C3 cannot be activated?
- severe susceptibility to bacterial infections
- increased risk of development of connective tissue disease
since all 3 pathways activate C3 and follow the common pathway at the end, what happens if there is a defect and the common final pathway cannot be activated?
- inability to make MAC
- inability to use complement to lyse encapsulated bacteria
- specific hole in immune system: N. meningitis, Strep. pneumonia, H. influenza
what are some secondary potential causes of complement deficiency?
- active lupus
- nephritic factors
how do we investigate a possible complement deficiency?
- C3
- C4
- CH50 (classical)
- AP50 (alternative)
spot diagnosis: membranoproliferative nephritis and bacterial infections
a) C9 deficiency
b) C3 deficiency with presence of nephritic factor
c) MBL pathway deficiency
d) C1Q deficiency
b) C3 deficiency with presence of nephritic factor
spot diagnosis: spot diagnosis: severe childhood onset SLE, normal levels of C3 & C4
a) C9 deficiency
b) C3 deficiency with presence of nephritic factor
c) MBL pathway deficiency
d) C1Q deficiency
C1Q deficiency (problems with classical pathway activation)
spot diagnosis: meningococcus meningitis with family history of sibling dying of same condition as child
a) C9 deficiency
b) C3 deficiency with presence of nephritic factor
c) MBL pathway deficiency
d) C1Q deficiency
C9 deficiency (problems with common pathway --> MAC)
spot diagnosis: recurrent infections when receiving chemotherapy but previously well
a) C9 deficiency
b) C3 deficiency with presence of nephritic factor
c) MBL pathway deficiency
d) C1Q deficiency
MBL deficiency
what are cytokines (and list some examples)?
-small protein messengers of immunomodulatory function
-autocrine or paracrine dependent action
Examples: IL2, IL6, IL10, IL12, TNF, TGF
what are chemokines (and examples)?
-chemotactic chemokines are chemoattractants for the direct recruitment/homing of leukocytes in an inflammatory response
Examples: CCL19, CCL21, IL8, MIP1 alpha/beta
what type of hypersensitivity is in contact dermatitis?
type IV
symptoms occur 24-48 hours after exposure… itchy & rash. Not responsive to anti histamines.
when might we see rouleaux formation?
multiple myeloma
how does HIV work?
it is a retrovirus that replicates inside cells using an enzyme called Reverse Transcriptase (RT) to convert RNA into DNA which can be integrated into host cell’s genes. Prefers CD4+ T helper cells as host targets.
what is the organization of the HIV virus?
- Icosahedral (20-faced tr).
- Slow developing disease
- Genome is diploid, (+)ssRNA
- 9 genes (e.g. env, gag, pol) (tat, rev, nef) (vif, vpr, vpu) encoding: 15 Proteins.
why does the immune system fail to protect against HIV infection?
- the CD4+ T helper cells are the target of the virus. *Progressive decline in CD4 T-cell function & numbers
- HIV-1 can also be trapped by FDC when enters the lymph node
