Immunology Flashcards
What are the physiological functions of mucosal tissues?
Gas exchange
Food absorption (vitamin absorption and production)
Sensory activities
Reproduction
As well as portals of entery for pathogens, mucosal surfaces are also portals of entry for non pathogenis antigens. T of F?
True. Things like food.
What type of epithilium lines the small intestine?
Single columnar epithilium
Define transcellular and paracellular
Transcellular = transport through a cell eg glucose from the lumen to the blood Paracellular = transport between cells- in the interstitail fluid
What are the mucosal organs of the human?
Salivary gland, mamory gland, kindeys, Uterus, bladder and vagina
What are the mucosal surfaces of the body?
Conjunctiva, oral cavity, Trachea, sinus, lungs, oesophagus, stomach, lange and small intestines uterus, bladder and vagina
An immune response at one mucosal site can initiate an immune response at all mucasal sites?
Yes
What are the secondary lymphiod tissues?
Lymph nodes and spleen
What are the primary lymphiod tissues?
Bone marrow and thymus
Where are lymph nodes located?
All mucosal surfaces
How do dendritic cells enter lymph nodes?
Afferent lymph vessels
How do T and B lymphocytes enter lymph vessels?
In the blood
Where do antigen presenting cells go when they first enter the lymph node?
Paracortical area and look for a T cell with a TCR complementary to the MHC class 2 protein and peptide antigen
Where are classical lymph nodes found?
In the messentary- not the gut wall
What is an intra epithilial lymphocyte?
CD8+ T lymphocytes
Where are the antigens detected in the small intestine?
Peyers patch
Where are the antigens detected in the large intestine?
Isolated lymphoid follicle
Where iare the immune effector functions taking place in the gut?
Lamina propria
What effector cells can be found in the lamina propria?
All the immune cells from the blood
How do antigen presenting dendritic cells get to lymph nodes in the mesentary?
Afferent lymph vessels
What epithilium covers the peyer’s patch?
Dome epithilium
What are M cells and where are they found?
M cells are ‘microvilli’ cells as they increase the surface area for sampling antigens. Found just above the peyer’s patch interspersed in the epithilial cells
Where are dendritic cells found in the Peyer’s patch?
Directly under M cells with dendritic processes within the M cells
When a dendritic cell presents an antigen with in the peyer’s patch, what happens next?
Activates T cells partially which then travel to lymph nodes in the messentry to be fully activateand then directed back to the lamina propria of the intestine.
Are germinal centres present in peyer’s patches?
Yes
How do M cells take up antigens from the lumen and how do they become bound to dendritic cells?
Endocytosis or phagocytosis. It is transported across the M cell in vesicles and released at the basal surface where the antigen is bound to dendritic cells
Can dendritic cells extend processes across the epithilial layer to directly capture antigens from the lumen of the gut withiut an M cell?
Yes. This happens in the lungs and GI tract
What are the immune cells of the epithilial layer in the gut?
Dendritic cells
CD8+ T lymphocytes are intraepithilial lymphocytes
What are the immune cells of the lamina propria?
Dendritic cells, Macrophages, CD4+ T cells, Mast cells, Plasma cells, IgA
What are plasma cells?
Termiinally differentiated B cells which produce antibodies
What directs unactivated T cells into the Peyer’s patch from blood vessels?
Homing receptors CCR7 and L-selectin
How do activated T cells in the mesenteric lymph nodes get back to the gut where the infection is?
Drain into the thoracic duct and enter the blood stream via the left venous angle.
The activated T cells express alpha4 beta 7 integrin and CCR9 which hone on the lamina propria
What molecules does the endothilium in the get express which enables activated T cells to bind and transendothilially migrate into the lamina propria?
MAdCAM-1
MA = Molecular adressin
Activated T cells in the lamina propria migrate to the gut epithilial cells due to what?
Chemokines expressed by the epithilial cells which the activated T cells have receptors for
MAdCAM is also found in the vasculature of other mucosal sites. What are the implications for this?
An immune response in the gut will also produce an immune response at other mucosal sites because the lymphocytes primed in the gut can migrate
There is a unified reirculation compartment meaning there is a common mucosal immune system. T or F?
True
What is the beifit of the common mucosal immune system for babies?
The antibodies and being produced in response to the pathogens in the mothers gut can be transferred to the baby for passive immunity through breast milk
What challenges does the mucosal immune system present?
Vaccine development. Hard to create a vaccine that is given systemically that will elicit a mucosal response. Eg HIV for which the primary infection site is the urogenital tract.
Which antibodies are produced by the mucosal response in the gut?
80% IgA
15% IgM
5% IgG
What is special about mucosal IgA?
IgA1:IgA2 ratio is 3:2 (its 10:1 in peripheries)
IgA2 is less prone to cleavage by enzymes than IgA1
IgA is a dimer in mucosal tissue and a monomer
in periferies
What is the J chain?
Joining chain connecting 2 IgA monomers to produce a dimer
How is IgA secreted into the lumen?
IgA dimer released from plasma cells in the lamina propria binds to the poly Ig receptor on the basolateral surface of epithilial cells.
The antibody receptor complex is endocytosed and travels to the apical membrane where it is released with the a secretory component
What is the function of the secretory component of IgA?
It wraps around the hinge region which is most prone to enzymatic cleavage. Protects the IgA.
What is the functions of sIgA in the gut?
1) Bind and neutralise pathogens and toxins in the lumen
2) Bind and neutralise antigensin internalised endosomes
3) Export toxins from the lamina propria while being excreted
The IgA secreted by plasma cells is specific to what?
The antigens that were detected in the peyer’s patch
1 in 300 people are IgA deficient in Tayside. Why are they asymptomatic?
IgM can replace IgA because the poly Ig receptor on the basolateral membrane of epithilial cells can also bind IgM because it is a polyer too (pentemer)
Intraepithilial lymphocytes are mostly CD8+ T cells. What are the featres of these cells?
Fully activated for killing (no cytokines required)
Restricted antigen receptors so are very specific
What immune cell is responsible for coelliac disease?
Intraepithilial lymphocytes
What anchors intraepithilial cells into the membrane (every 10 cells) to prevent them moving?
AlphaEpsalon:Beta7 integrins
What types of cells will intraepithilial cells kill?
Virally infected mucosal cells with MHC class 1
Epithilial cells under stress due to infection, damage or toxins which express MIC-A and MIC-B
which binds to NKG2D on IEL
How do intraepithilial cells kill detected cells?
Perforin/granzymes
Fas dependent pathways
Only kill specific cells- not surrounding cells
What happens if intraepithilial cells are killing more cells than epithilail stem cells are producing?
Flattened epithilium and reduced absorption. CLinically present with mal absorption
How does coelliac disease present?
Malabsorption
What is oral tollerence?
Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion.
Why are T cell and IgE mediated responses inhibited more than serum IgG in oral tolerance?
Because T cells and IgE cause the most damage
What are the mechanisms of mucosal HYPOresponsiveness for food?
1) Commensal organisms of the gut
2) Anergy or deletion of antigen specific T cells => no costimulation
3) Generation of T reg cells which => T helper 3 cell production. Suppresses the immune system and switching B cells to IgA production
Toll Like receptors recognise a ‘pathogen’ (food) which activates IKK. IKK phosphoryates IkB so its degraded and NFkB can translocate to the nuclus for gene transcription. How can this be prevented?
Commensal bacteria can activate PPARgamma which removes NFkB from the nucleus
OR commensal bacteria can block degradation of phosphorylated IkB so NFkB cannot translocate to the nucleus
What do commensal bacteria produce that inhibits dendritic cell maturation?
TGF beta and TSLP
What response do immature and mature dendritic cells initiate?
Immature => weak co-stimulation => T reg cells and T helper 3 cells
Mature => strong co-stimulation =>T helper 1 and T helper 2 cells
Can you summarise the mucosal response to infection with a pathogen to the point of activating immune cells?
1) Bacteria are endocytosed and recognosed by toll like receptors in vesicles or bacteria directly enter the cytosol of the epithilial cells and recognised by NOD1/2.
2) These activate the NFkB pathway => gene transcription and production of cytokines, chemokines and defensins.
3) These activate macrophages neutrophils and dendritic cells.
The outcome of an infection by a pathogen can have a protective or a damaging effect on the host. What determine what type of effect is produced?
Immunogenetics. Some people have a very protective effect, for some there is more damage but there is a sliding scale.
Helminth infection: nieve CD4+ T cells are activated and what will produce a protective response?
T helper 2 cells.
1) Produce IL13
2) Produce IL5
3) Stimulate B cells to produce IgE
4) Produce IL3 and IL9 which drive mast cell recruitment (important in helminth infections)
Helminth infection: What does the production of IL13 lead to?
Epithilial cell repair and mucus.
Increased cell turnover aids sheeding of infected
cells and mucus helps sweep things out of the GI tract
Helminth infection: What does IL5 lead to?
Recruitment and activation of eosinophils which produce MBP which kills paracites and mediates ADCC. It also promotes IgA production
Helminth infection: What does production of IL3 and IL 9 lead to
Mast cells to produce mediatiors like histamine, TNF alpha that recruit inflammatory cells and remodel the mucus
Helminth infection: nieve CD4+ T cells are activated and what will produce a damaging response?
Production of T helper 1 cells
1) Activate macrophages
2) Activate B cells to produce IgG
Helminth infection, what is the consequence of Th1 cells activating macrophages?
Production causes tissue damage and tissue remodelling and release of pro inflammatory cytokines
Helminth infection, what is the consequence of Th1 cells activating B cells to produce IgG?
I gG is a complement fixing antibody which is useless in helminth infections. Need antibodies bound to mast cells eg IgE
What happens when the mucosal surface is exposed to HIV?
1) HIV invades dendritic cells which become activated and then migrate to the lymph nodes in the mesentery.
2) Nieve CD4+ T cells in the lymph nodes become infected and activated.
3) Activated T cells then move migrate back to the mucosal surface due to molecular adressins and HIV invades all the CD4+ T cells in the mucosal membranes.
HIV will kill 50-75% of memory T cells in the mucosal membrane. => Secondary immunodefficiency
2/3 of people with selective IgA deficiency are assymptomatic. What type of infections are common in symptomatic individuals?
Sinopulmonary BACTERIAL infections.
Also coelliac disease is 10x more common in those with IgA deficiency
What is CVID?
Common varient immunodefficiency is a primary immunodeficiency.
When does CVID present?
Adulthood
What are the common infections in those with CVID?
Recurrent sinopulmonary and GI infections. BACTERIAL
What is the cause of CVID?
Failure to differentiate B cells in to Ig secreting plasma cells => Low IgG, IgA, IgM and IgE. This effects the adaptive immune response
CVID has a diagnostic delay of 5-7 years. WHat is the consequence of this?
When CVID is picked up late they have bronchiectasis
How is CVID treated?
Immunoglobulins
What is XLA?
X linked agamaglobulemia. Affecting boys. Do not produce B cells or IgG
When does XLA present?
7-8 months when maternal IgG is weaning
What are the common infections in someone with XLA?
Sinopulmonary and GI infections. Bacterial.
and devastating manifestations of enteroviral infections.
How is XLA treated?
Replacement immunoglobulins
What is CGD?
Chronic granulomatous disease is caused by failure of the phagocyte respiratory burst
What is the phagocyte respiratory burst?
NADPH oxidase => superoxide => reactive free radicals => kill pathogens
WHat are the common infections in those with CGD?
Staph aureus, inflammatory granulomas, pneumonia, liver abscess, perianal abscess and skin abcess
How many genes can cause CGD?
4
1 is X linked and 3 are autosomal recessive
How is CGD treated?
Bone marrow transplant
What is SCID?
Severe combined immunodefficiency. T cell gene defect which leads to a B cell defect.
When does SCID present?
First weeks of life
What are the common infections with SCID?
Oral candiditis, chronic diarrhoea, intestinal pneumonitis, rota virus, EBV
Can haloallegens produce anaphylaxis?
No (thats things like pollen, dust mites etc)
What is a food allergy?
Type 1 hypersensitivity reaction initiated by cross linking of allergen specific IgE bound to mast cells by Fc receptors with the specific allergen. Memory response- immune system must be primed.
What are the classic triggers for anaphylaxis?
Venom and drugs because they are given systemically
What is the common presentation of food allergy?
D&V, anaphylaxis is uncommon
Whay can food cause anaphylaxis?
Absorption of whole food proteins across the gut- specific proteins which are very stable and not broken down by heat or gut enzymes
What type of immune respose is an allergy?
Adaptive, IgE mediated
Why is avoidance the best advice for someone with a food allergy?
The more times you present and antigen to the immune system the better (worse for the patient) the response is
What is coeliac disease??
Gluten sensitive enteropathy
Is coeliac disease an allergy?
No- its T cell mediated and is a hypersensitivity reaction
What is the genetic susceptibility for coeliac disease?
HLADQ2- 95% of those with coeliac have this gene
HLADQ8- 5% of people with coelliac disease have this gene.
Why is genetic testing not really useful for coeliac disease?
Because 20% of the general population haev HLADQ2 and they do not have coeliac disease
What are the main immune cells involved in coeliac disease?
T cells and intraepithilial lymphocytes
Once a gluten specific T cell is activated what happens?
interferon gamma from the T cell activates epithila cells which produce IL15 which induces proliferation and activation of intraepithilial lymphocytes. Both T cells and IEL can kill epithilial cells under stress
When does coeliac present
Any age
Most often 20-40
What are the macro and histopatholocial findings in coeliac disease?
Scalloping, Flattened epithilium/villous atophy, Only crypts remain.
Which sub molocule of gluten produces coeliac disease?
Gliadin
Gluten is found in rye, wheat and barley
Why are IgA antibodies for anti-gliadin and anti tissue transglutaminase produced in coelic disease?
Because when Gliadin passes through the epithilium it combines with the tissue transglutaminase enzyme and forms a complex which an antibody is produced for
Activation of a CD4+ T cell in coeliac disease leads to activation of which other immune cells?
T helper 1 cells, CD8+ T cells and NK cells which all produce cytokines which damage enterocytes
How is coeliac disease diagnosed in an adult?
Serology using IgA antitissue transglutaminase auto antibodies is used to triage cases for biopsy.
A biopsy is the gold standard test
How is coeliac disease diagnosed in children?
Non biopsy diagnosis. Biopsy would require GA in a child Serology test using IgA antitissue transglutaminase auto antibodies.
The IgA antitissue transglutaminase auto antibodies test is 95% sensitive and 97% specific but what is the patient group for which this test is uninformative? What must be done to diagnose coeliac disease?
Thise with IgA deficiency. You get false negatives because they cannot produce IgA in the first place. They are also 10x more likely to have coelic so you must do a biopsy
Patient: I have been having trouble with my diet ect but I have cut gluten out and no I fell better, can you just do the test for coelliac disease please?
No because you must have been eating gluten for 6 weeks before the test.
No gluten = no anti-tissue transglutaminase antibody
Apart from diagnosis of coelliac what is the other use of IgA antitissue transglutaminase (IgA anti TTG) auto antibodies test?
Dietary compliance monitoring. No gluten in diet = No autoantibody
What are the causes of persistent symptoms in coeliac disease?
Lack of dietary compliance Rarely T cell lymphoma
What is the best antigen presenting cell in a primary and secondary immune response?
Primary = dendritic cell Secondary = B cell
Why is an AUTO antibody formed in coelic disease?
The gluten-
TTG complex binds to the B cell antigen on the TTG part, not the gluten part => anti TTG antibodies produced which attack self cells
What part of the GI tract does Chron’s disease affect?
Any pary from mouth to annus. Most common in the terminal illeum and colon
What are the characteristic tissue chages of Crohn’s disease?
Focal and discontinuous inflammation with granulomas. Very inflammatory T cell response
There are over 200 genes associated with crohn’s disease. WHat is the nmost common?
NOD2 deficiency
Where does ulcerative colitis effect the gut?
Begins in the rectum and moves proximally and continuously to the colon
Which of UC and Crohns have extra intestinal symptoms?
Both
What are the characteristic tissue changes in UC?
Distortion of the crypts with infiltration of monocytes, neutrophils and plasma cells. Inflammation only in surface mucosa
What is the treatment for Crohns and UC?
Steroids and immunosupressive drugs
Anti TNF alpha
