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Year 1: Respiratory > Respiratory Immunology > Flashcards

Flashcards in Respiratory Immunology Deck (99):

what are 2 cytokines which induce an anti-viral state?

IFNa and IFNb


Name some pro-inflammatory mediators (produced by activated macrophages, mast cells, neutrophils)

and others...


Which mediator induces the production of ROS/ RNS by macrophages? Secreted by what?

IFNg (which is secreted by activated NK cells and effector Th1 cells)


Which mediator, secreted by Th cells, promotes proliferation and differentiation of activated CD4+ and CD8+ cells?



Which cytokines are secreted by Th1 cells? What do they do?

IFNg, IL-2, TNFa: increases proliferation and activity of macrophages, NK and CD8+ cells , increased proliferation of B cells and production of opsonising Ig (IgG, IgM and IgA), IL-2 and IFNg positively feedback for Th1 production, IFNg inhibits Th2 production.
(for clearance of bacteria, viruses, fungi (intracellular!), promotes inflammation, autoimmune disease, lots of IFNg = fibrosis)


Which cytokine, secreted by Th0 cells, stimulates differentiation into Th1?



Name an anti-inflammatory cytokine

IL-10 (secreted by macrophages once the pathogen has been eliminated)


Which cytokine, secreted by Th0 cells, stimulates differentiation into Th2?



Which cytokines are secreted by Th2 cells? What do they do?

IL-4, IL-5, IL-10, IL-13
IL-10 is anti-inflammatory
IL-4 positively feedbacks for Th2 cell production, and increases proliferation and activation of eosinophils and mast cells
IL-5 increases proliferation of B cells and class switching to IgE
IL-13 is for airway hyperresponsiveness and mucus hypersecretion
Functions: clearance of parasites (helminths), suppression of inflammation, and allergy and asthma


Which cytokines, secreted by Th0 cells, stimulate differentiation in Th17?

IL-6 and TGFB


Which cytokines does Th17 secrete? What are their functions?

IL-17 and IL-22
IL-17 affects epithelium, causing increased recruitment of neutrophils
Il-22 increases cytokine and chemokine production by many cells
Function: clearance of bacteria and fungi (extracellular), promotes inflammation, autoimmune diseases, increased neutrophil infiltration in severe asthma


Which cytokine, secreted by Th0, stimulates differentiation into Treg (T regulatory cell)?



Which cytokines does T-reg secrete? What are the functions?

Decreases the function of macrophages and APCs
Decreases secretion of pro-inflammatory cytokines
Overall: function is suppression of immune response, and protection against autoimmunity



development of active immunity through exposure to a less virulent pathogen


toxoid vaccine

these are for bacteria which secrete toxins
The toxins are detoxified with formalin and so are safe for use in a vaccine. When the immune system receives a vaccine containing a harmless toxoid, it develops active immunity against the natural toxin.
e.g. vaccines against tetanus and diphtheria


what are the 3 types of inactive vaccine?

-killed/ attenuated


features of attenutated (killed) vaccines?

-cannot replicate
-not as effective as live vaccines
-may need boosters
-immune response is primarily antibody based (not T cells)


what type of vaccine is the salk polio vaccine?

administered by injection
needs 3 doses
more expensive than salk


define adjuvants

things added to vaccine to modify the immune response by boosting it, such as to give a higher amount of antibodies and a longer-lasting protection, thus minimising the amount of injected material


benefits of inactivated vaccines?

-usually safe (CAN be given to IC individuals)
-no refrigeration required
-can be made quickly


disadvantages of inactivated vaccines?

-difficult to stimulate an immune response to many killed organisms
-poor at eliciting T cell responses
-memory is variable so boosters needed


examples of whole cell inactivated vaccines?

polio (salk, inactivated), Hep A, rabies, cholera ,plague


examples of fractional (subunit) inactivated vaccines?

hep B, influenza, acellular pertussis, HPV, anthrax


examples of toxoid inactivated vaccines?

diphtheria, tetanus


subunit vaccines

these include only the antigens that best stimulate immune system (e.g. just epitopes sometimes)
chances of adverse reactions are low


polysaccharide vaccines

bacteria may have polysaccharide sugars on outer capsule, but these generate antibodies with less functional activity - especially in immature immune system
Immunogenicity can be improved by conjugating with an adjuvant (making it into a conjugate vaccine)
Conjugate vaccines convert polysaccharide antigens to protein to ensure there is a B AND T cell response


examples of polysaccharide only vaccine?



examples of polysaccharide conjugated to toxin vaccine?

-Haemophilus influenza type B vaccine
-prevenar (pneumococcus)


live attenuated vaccines

these contain a weakened version of the living microbe - so can't cause disease. These elicit strong response and give lifelong immunity with just one or two doses. IC people cannot have live attenuated vaccines because there's a chance it could cause disease


what is the process of "passaging" (which is used in making a live attenuated vaccine)?

subculturing of cells--> they get mutations in their new environments, which make them work less well in humans --> so they can then be safely used to vaccinate humans


examples of live attenuated vaccines?

Viruses: measles, mumps, rubella, chickenpox, yellow fever, rotavirus, smallpox (vaccinia), polio
Bacterial: BCG, oral typhoid


what type of vaccine is sabin polio vaccine?

live attenuated
elicits good antibody response in humans
administered orally (by dropper or on sugar cube)
contains all 3 strains of polio
full immunity requires 3 separate doses (as each strain dominates the response once)
unsafe in IC people
cheap vaccine


what are sources of passive immunity?

maternal antibodies (active transport of maternal IgG in third trimester, breast milk and colostrum contain IgA), therapeutic passive immunisation (pooled normal human immunoglobin, hyperimmune globin, heterologous hyperimmune serum, monoclonal antibody against specific pathogen


what is pooled immunoglobin?

transfer of antibody from an unrelated individual


what is hyperimmune globin?

Ig from an individual known to have high Ig levels against a specific pathogen


passive immunisation with monoclonal antibody

mab produced against RSV
given in severe LRTI in high-risk infants, severe CHD, pre-term infants, severe chronic lung disease in under 2 year olds
this provides short term protection
intramuscular injection during RSV season


Why is it difficult to develop vaccines for some organisms

-chronic or latent infections (TB, Hep C, HIV, Herpes virus)
-rapidly evolving infections (HIV, influenza)


hallmarks of immune deficiency

Serious, Persistent, Unusual, Recurrent infections


what are features other than SPUR that suggest primary immune deficiency?

-weight loss or failure to thrive
-severe skin rash
-chronic diarrhoea
-mouth ulceration
-unusual autoimmune disease
-family history


what are the differences between primary and secondary immune deficiencies?

-secondary are common, primary are rare
-secondary are acquired, primary are hereditary


what are some conditions associated with secondary immune deficiency?

immunosuppressive therapy
anti-cancer agents
cancer of the immune system (lymphoma, leukaemia, myeloma)
metastatic tumours
renal insufficiency/ dialysis
type 1 and type 2 diabetes
specific mineral deficiencies e.g. zinc, iron


clinical features of phagocyte deficiencies?

-recurrent infections at common or unusual sites
-common bacteria (e.g. Staph aureus) or unusual bacteria (e.g. Burkholderia cepacia)
-mycobacteria (both TB and atypical mycobacteria)
-fungi (candida, aspergillus)


What is the life cycle of a neutrophil?

Stem cells produce neutrophil precursors
Phagocytes and precursors move from bone marrow or from tissues to the blood
There is upregulation of endothelial adhesion markers (acute inflammation occurs). Neutrophils adhere and migrate into tissues
Neutrophils recognize and kill organism
They may activate other components of the immune system


failure to produce neutrophils

This is failure of stem cells to differentiate along myeloid (bone marrow) lineage
Primary defect: Reticular dysgenesis
Secondary defect: after stem cell transplantation

Or could be specific failure of neutrophil maturation: Kostmann syndrome, Cyclic neutropaenia


reticular dysgenesis

most severe form of SCID
absence of neutrophils and other myeloid cells and almost complete deficiency of lymphocytes in peripheral blood and lack of innate and adaptive humoral and cellular immunity - leads to fatal septicaemia within days of birth. RBC and platelet production is not affected.


Kostmann syndrome

Group of diseases that affect myelopoiesis (production of bone marrow and all the cells that arise from it) - causing severe congenital neutropaenia
It's a failure of neutrophil maturation


cyclic neutropaenia

rare blood disorder in which there are recurrent episodes of abnormally low neutrophil levels (every 4-6 weeks)


management of Kostmann syndrome

-Supportive treatment: prophylactic antibiotics, prophylactic antifungals, without treatment there is 70% mortality within 1st year of life
Definitive treatment: stem cell transplant, give Granulocyte colony stimulating factor (G-CSF) - stimulates bone marrow to produce granulocytes and stem cells to release them into bloodstream


Leukocyte adhesion deficiency

failure to recognise activation markers expressed on endothelial cells. Neutrophils are mobilised, but cannot exit bloodstream
It's a rare, primary immunodeficiency, caused by genetic defect in leukocyte integrins (CD18)


Clinical feature of Laeukocyte Adhesion Deficiency

-recurrent bacterial and fungal infections
-very high neutrophil blood counts (leucocytosis, which is high WBC count - usually associated with infection)
-site of infection is in deep tissues, with NO pus formation


Defects of direct recognition

direct recognition is by PRRs and PAMPs
PRRs recognise bacterial sugars, LPS
there is genetic polymorphism: some of which are associated with increased susceptibility to bacterial infection, but most don't cause significant disease


Defects of indirect recognition

Indirect recognition is by opsonins (e.g. complement, antibodies, CRP)
-opsonins bind to receptors on phagocyte surface
BUT defects in opsonin receptors may cause defective phagocytosis
This generally doesn't cause significant disease
ALSO, any defect of complement or antibodies will result in decreased efficiency of opsonisation


failure of oxidative killing mechanisms: chronic granulomatous disease

-absent respiratory burst (and so a deficiency of intracellular killing mechanisms of phagocytes, and an inability to generate ROS/ RNS), impaired killing of intracellular microorganisms
CGD is a diverse group of hereditary disease in which certain cells of the immune system have difficulty forming ROS used to kill certain ingested pathogens - leading to an inability to clear organisms, failure to degrade chemoattractants and antigens, persistent accumulation of neutrophils and activated macrophages and lymphocytes - leading to the formation of granulomas in many organs


features of chronic granulomatous disease

recurrent deep bacterial infections
recurrent fungal infections
failure to thrive
lymphadenopathy and hepatosplenomegaly
granuloma formation


what's a lab investigation of chronic granulomatous disease?

-NBT (nitroblue tetreazolium test)
- tests whether neutrophils are able to kill through production of ROS
-method: feed their neutrophils E-coli, add dye that is sensitive to H2O2, if H2O2 is produced by neutrophils - the dye changes colour


treatment of chronic granulomatous disease?

-supportive: prophylactic antibiotics and antifungals
-definitive treatment: stem cell transplant, gene therapy


what are defects that could cause problems in defence against intracellular organisms?

(defects in the IL-12: IFNg interaction)
-single gene defects: IFNg receptor deficiency, IL-12 deficiency, IL-12 receptor deficiency
-these defects could lead to TB, atypical mycobacterial infection, salmonella


treatment of phagocyte deficiencies

-aggressive infection management: prophylaxis (septrin, intraconazole), oral. IV antibiotics, surgical drainage of abscesses
-definitive therapy (bone marrow transplant)
Specific definitive therapy for CGD: gamma interferon therapy, gene therapy


how many hours after infection are the innate, and acquired immune response active?

innate = 0-4 hrs
acquired = >96 hrs


what are Peyer's patches?

these are aggregated lymphoid nodules. They are an important part of gut associated lymphoid tissue and are usually found in humans in the lowest portion of the small intestine (mainly in the distal jejunum and the ileum).


What's the life cycle of a T lymphocyte?

1. Arises from haematopoetic stem cells in bone marrow
2. Exported as immature cells to the thymus
3. In thymus, undergoes selection - only 10% cells survive. Those that survive proliferate and mature
4. Mature T lymphocytes enter circulation and reside in lymph nodes and secondary lymphoid follicles. There are billions of distinct T cell clones


CD4+ T lymphocytes

These have immunoregulatory functions: they provide co-stimulatory signals which are necessary for activation of CD8+ (produce IL-2, which is a mitogen for both CD4 and CD8 cells) and naïve B cells (provide signal 2 - needed for B cell proliferation, they also provide CD40L) and also for influencing phagocyte function, they produce cytokines, they regulate other lymphocytes and phagocytes
They recognise peptides presented on HLA class II molecules


Which cytokines stimulate CD4+ to produce IFNg?

IL-12 and IL-2


CD8+ T lymphocytes (cytotoxic)

These recognise peptides in association with MHC class I (HLA class I)
They kill cells directly: production of pore-forming molecules e.g. perforin, triggering apoptosis of the target, secreting cytokines e.g. IFNg
CD8+ are important in defence against viral infections and tumours


B cells

These arise from haematopoetic stem cells in bone marrow
Mature B cells are found mainly in bone marrow, lymphoid tissue, spleen
Functions: antibody production and antigen presentation


B lymphocyte development

In bone marrow: Stem cells - lymphoid progenitors - pro B cells - pre B cells
Then export of IgM B cells from bone marrow: IgM B cells develop into either IgM/ IgA/ IgE/ IgG B cells, which then develop into IgM/ IgA/ IgE/ IgG plasma cells


activation of B lymphocytes

They encounter antigen in lymph nodes
If provided with appropriate signals from T lymphocytes: stimulated B cells rapidly proliferate
They undergo genetic hypermutation
Then there is further differentiation into long-lived plasma cells and plasma cells which produce antibody


What condition can cause failure of differentiation of myeloid lineage (and so cause failure of production of lymphocytes, neutrophils...)

reticular dysgenesis


what is the term for defects of lymphoid precursors?

Severe combined immunodeficiency (SCID)


clinical phenotype of SCID?

-unwell by 3 months old (maternal IgG from placenta crossing protects the SCID neonate for first 3 months)
-failure to thrive
-persistent diarrhoea
-SPUR infections
-vaccine associated disease
-unusual skin disease
-Graft versus host disease (colonisation of infant's "empty" bone marrow with maternal lymphocytes
-family history of early infant death


Graft versus host disease

Condition that might occur after an allogenic (immunologically incompatible) transplant. In GvHD, the donated bone marrow or peripheral blood stem cells view the RECIPIENT'S body as foreign, and the donated cells/ bone marrow attack the body.



an immune disorder characterised by a reduction in all types of gamma globulins, including antibodies that help fight infection. It may be congenital/ related to medication/ due to a kidney or GI condition/ cancer/ severe burns.


Causes of SCID

There are over 20 possible pathways:
-deficiency of cytokine receptors
-deficiency of signalling molecules
-metabolic defects
-defective receptor rearrangements
In SCID, there are different lymphocyte subsets - depending on the exact mutation


x-linked SCID

-45 % of all SCID
-caused by mutation of a component of IL-2 receptor (which is shared by many other cytokines, resulting in inability to respond to cytokines: so failure of T cell and NK cell development, and immature B cells are produced


clinical phenotype of x-linked SCID?

-very low/ absent T cells (because IL-2 is so important for T cell development)
-normal or increased B cells
-poorly developed lymphoid tissue and thymus


treatment of SCID?

-prophylactic: avoid infections (prophylactic antibodies, antifungals, no vaccines), aggressive treatment of infections, antibody replacement by IV Ig
-Definitive treatment: stem cell transplant from HLA identical sibling, SCID patients are ideal for gene therapy (stem cells can be treated ex vivo to express missing component)


DiGeorge Syndrome

developmental defect of 3rd/ 4th pharyngeal pouch, due to deletion at chromosome 22q11.
It's a complex disorder. Results in failure of thymic development, leading to T cell immunodeficiency (nowhere for T cells to mature), congenital heart defects, cleft palate, hypocalcaemia secondary to hypoparathyroidism, developmental delay, psychiatric disorders


What kind of infections will someone with DiGeorge syndrome get?

-recurrent viral: due to CD8 cells being essential in killing of virally infected cells
-recurrent bacterial: due to T cells being essential in helping B cells make Ig
-frequent fungal: due to T cells being essential for fungal defence


In lab blood tests of someone with DiGeorge Syndrome, what would be found (regarding T cells, B cells, NK cells)?

-absent or decreased no. of T cells (and defective T cell activation response)
-normal or increased B cells (low IG, IgA, IgE, and poor Ig responses to specific pathogens)
-normal NK cell numbers


management of DiGeorge Syndrome

-correct metabolic and cardiac abnormalities
-prophylactic antibiotics
-early and aggressive treatment of infection
-some patients need Ig replacement
-T cell function improves with age (possible extrathymic maturation of T cells)


what are disorders of T cell effector function?

-cytokine production
-T-B cell communication


defect of T cell effector function: cytokine production
And what types of infection could this lead to?

This is a deficiency resulting in susceptibility to infection (e.g. defects in IL12, IL12 receptor, IFNg, IFNg receptor)
Could lead to : TB, atypical mycobacteria, BCG infection after immunisation, deep fungal infections such as aspergillus


Bare lymphocyte syndromes (a failure of expression of HLA molecules)

condition caused by mutations in certain genes of the MHC or involved with the processing and presentation of MHC molecules. It's a form of SCID, BUT as a contrast to SCID: bare lymphocyte syndrome doesn't cause decreased T and B cell counts, as the development of these cells is not impaired. Diarrhoea can be among associated conditions.


Autoimmune lymphoproliferative syndromes (ALPs) (failure of normal apoptosis)

rare genetic disorder of abnormal lymphocyte survival caused by defective Fas mediated apoptosis. Normally after infectious insult, the immune system down-regulates by increasing Fas expression on activated B and T lymphocytes and Fas-ligand on activated T lymphocytes. Fas and Fas-ligand interactions trigger apoptotic cascade - leading to apoptosis. Patients with ALPs have a defect in this apoptotic pathway - leading to chronic non-malignant lymphoproliferation, autoimmune disease and secondary cancers


clinical features of T cell deficiencies

-recurrent infections (viral, bacterial, fungal, intracellular pathogens e.g. mycobacteria)
-opportunistic infections
-malignancies at young age
-autoimmune disease


Investigation of T cell deficiencies

1st line:
-total WCC and differential
-serum Ig and protein electrophoresis (surrogate marker of functional T cells)
-quantitation of lymphocyte subpopulations
2nd line:
-functional test of T cell activation and proliferation (may be useful if signalling or activation defects are suspected)
-additional tests of lymphocyte lineage
-an HIV test is essential


clinical presentation of Ig deficiencies

-recurrent bacterial infections (upper and lower respiratory tract, recurrent GI infections, often common organisms, viral infections are less common but may occur)


Name 2 antibody mediated autoimmune diseases

-idiopathic thrombocytopaenia
-autoimmune haemolytic anaemia


idiopathic thrombocytopaenia (an Ig mediated autoimmune disease)

This is an isolated low platelet count with normal bone marrow and the absence of other causes of thrombocytopaenia


autoimmune haemolytic anaemia (an Ig mediated autoimmune disease)

This occurs when antibodies directed against a person's own RBCs cause them to burst (lyse), leading to insufficient plasma concentration. Lifetime of RBCs is reduced to just a few days in serious cases. Intracellular components of the RBCs are released into circulating blood and tissues - causing characteristic symptoms


Bruton's x-linked hypogammaglobobulinaemia (failure to produce mature B cells)

This is a rare genetic disorder in which the WBC formation process doesn't generate mature B cells, which manifests as a complete or near-complete lack of proteins called gamma globuling, including antibodies, in the person's bloodstream. This impairs the immune system.
In this condition: there are on circulating B cells, no plasma cells, no circulating antibody after the first 6 months of life


selective IgA deficiency

prevalence = 1/600
2/3 are asymptomatic
1/3 have recurrent RTIs
There is a genetic component, but cause as yet unknown
This is a type of hypogammaglobulinaemia. Defined as undetectable serum IgA levels in the presence of normal serum levels of IgM and IgG. It's the most common of the primary antibody deficiencies. Most people with this are healthy and never diagnosed.


Common variable immune deficiency (CVID)

an immune disorder characterised by recurrent infections and low Ig levels, especially IgG, IgM and IgA. General symptoms include: high susceptibility to foreign invaders, chronic lung disease, inflammation and infection of the GI tract. Origins of CVID are poorly understood.
In CVID, there is: low IgG, IgA and IgE, recurrent bacterial infections, often associated with autoimmune disease


clinical features of CVID

-recurrent bacterial infections (often severe end-organ damage, bronchiectasis, persistent sinusitis, recurrent GI infection)
-autoimmune disease
-granulomatous disease


x-linked hyper IgM syndrome

This is caused by mutation of CD40LG gene (which codes for CD40 ligand- which is expressed on T cells). When CD40L binds CD40 on B cells, the B cell can then switch from producing IgM to producting IgA or IgG. In these patients, however, a lymph nodes biopsy may show poor development of structural and germinal centres because of lack of activation of B cells by the T cells in them


clinical features of B cell deficiencies

-recurrent infections (primarily bacterial, often common organisms)
-opportunistic infections
-Ig mediated autoimmune disease


management of B cell deficiencies

-aggressive treatment of infection
-Ig replacement (pooled plasma, containing IgG, administered by IV every 3-4 weeks, lifelong treatment)
-stem cell transplant


Differential diagnosis of recurrent bacterial infections and hypogammaglobulinaemia

-primary: antibody deficiency (CVID/ specific antibody deficiency/ other conditions which are rare in adults)
-secondary: protein loss (protein losing enteropathy/ nephrotic syndrome), or failure of protein synthesis (lymphoproliferative diseases such as chronic lymphocytic leukaemia/ myeloma/ non-Hodgkins lymphoma)


in the UK, what is the most important factor to take into account when allocating organs for transplant?

the outcome of the transplant
(a person's "value to society" should NEVER be taken into account)