Immunology Flashcards
what are the consequences of immune recognition
intended destruction of the antigen and incidental tissue damage
what are hypersensitivity reactions
immune response that results in bystander damage to the self
briefly describe the 4 types of hypersensitivity reaction
I: immediate killing
II: Direct cell killing
III: Immune complex mediated
IV: delayed type hypersensitivity
describe what type 1 reactions are characterised by (immediate killing)
characterised by greatly enhanced sensitivity to normally innocuous substances, leading to physiological responses and tissue damage
what do type I reaction leads to
allergic diseases and reaction, signs and symptoms
define an allergy in immunological terms
IgE-mediated antibody response to external antigen (allergen)
what is happening to the prevalence of allergies
increasing
what are common allergens that trigger allergic reactions
(most soluble proteins that function as enzymes)- dust mites, protein in animal saliva, pollen, food, drugs, bee and wasp venom
are all adverse reactions allergic
no
what is the hygiene hypothesis
changes in microbial stimuli influence the maturation of the immune response- results in increased predisposition to allergic conditions during childhood
why is allergy prevalence increasing and associated with western countries
the hygiene hypothesis- improved sanitation and decreased incidence of infectious disease
what enhances the immune system
exposure to bacteria or viruses e.g. infections contracted from siblings or peers at daycare centres
what happens to CD4 T lymphocytes at birth
primed to develop into TH2 cells
what does exposure to antigens do to the development of TH2 cells
dampens it, creating bias towards TH1 response- TH1 differentiation stimuli, limiting allergies and asthma
what are the generic features of type 1 allergic disease
occurs quickly after exposure to allergen (1-2 hours), reactions influenced by site of contact
what are the specific features of type 1 allergic disease
asthma, urticaria (hives), angioedema (swelling), allergic rhinitis (hayfever), allergic conjunctivitis, diarrhoea and vomiting, anaphylaxis
what immune cells are involved in allergic disease
b lymphocytes, t lymphocytes, mast cells (eosinophils and basophils)
how are B lymphocytes involved in allergic reactions
recognise antigen, produce antigen-specific IgE antibodies
how are T lymphocytes involved in allergic reactions
TH2 cells provide help for B lymphocytes to make IgE antibody
how are mast cells involved in allergic reactions
inflammatory cells that release vasoactive substances
what results in the differentiation of CD4 T cells into effector TH2 cytokine-producing cells
stimulation of allergen-specific T cells by allergen-derived peptides, presented by dendritic cells in the context of class II MHC molecules
what regulate the immune response
interleukins IL-4, IL-13, IL-5 produced by TH2 cells
how do interleukins regulate the allergic response (3)
regulate the synthesis of IgE by B cells, stimulate differentiation and migration of eosinophils from the bone marrow into the blood, helping to activate mast cells and eosinophils at sites of allergen exposure
how is the secretions of B cells altered by TH2
initially secrete IgM but initiated by TH2 cells to produce IgE
what does mast cells role in orchestrating the inflammatory cascade lead to
lead to increase blood flow, contraction of smooth muscle, increase vascular permeability and secretions at mucosal surfaces
what vasoactive substances do mast cells produce that drive acute inflammation
histamine, leukotrienes, pro-inflammatory cytokines including IL-4 and TNF-alpha
what do mast cells express on their surface
receptors for the FC region of IgE antibody on their surface
what happens to B cells on first encounter with allergen
produce antigen-specific IgE antibody
what happens to residual IgE antibodies
bind to circulating mast cells via Fc receptors
what is the region of the antibody that is specific to the antibody and where it binds to Fc receptors
the heavy chain
what happens when allergens re-encounter the IgE- coated mast cells
cell membrane disrupted and vasoactive mediators (histamine, tryptase) released. also increased cytokine and leukotriene transcription
what is atopic asthma
allergic disease in the lungs
is non allergic asthma IgE mediated
no
describe intrinsic asthma
non allergic
describe extrinsic asthma
response to external allergen, IgE-mediated
what happens clinically when histamine and other inflammatory mediators are released
muscle spasm, mucosal inflammation, inflammatory cell infiltrate
what are pro inflammatory mediators
pro inflammatory cytokines
what does muscle spasm lead to
bronchoconstriction; wheeze
what does mucosal inflammation lead to
mucosal oedema, increases secretions; sputum production
what does inflammatory cell infiltrate lead to
infiltration of lymphocytes and eosinophils into bronchioles; sputum (often yellow) (associated with chronicity)
what happens clinically when an allergic reaction happens in the lung
increased; mucous production, swelling, breathing rate
in and expiratory wheeze
what happens in degranulation of mast cells
when antimicrobial/cytotoxic molecules release from mast cells, when membrane disrupted
what is urticaria and how long does it last
hives, 2-6 (occasionally 24) hours
what is angioedema
self-limited, localised swelling of subcutaneous tissues or mucous membranes (non-pitting oedema
what are the clinical features of anaphylaxis
feeling of impending doom, loss of consciousness, death, angioedema of lips of mucosal membrane, stridor, laryngeal obstruction, hypotension, oral itching, vomiting, diarrhoea, abdominal pain, conjunctival infection, wheeze, bronchoconstriction, itch in palms, soles of feet and genitalia
why is it important to diagnose allergic disease (4)
confirm diagnosis, identify causative agents, determine risk of future severe reaction, determine appropriateness of therapy
name an elective investigation used to diagnose allergic disease
skin prick test
how can allergic disease be diagnosed during anaphylactic episode
evidence of mast cell degranulation (blood test- serum mast cell tryptase levels)
what is the first step in management of IgE mediated allergic disorders
indentification of triggers (skin prick test, clinical history, specific IgE tests) and avoidance of allergens
how is mast cell activation blocked?
via mast cell stabilisers (sodium cromoglycate)- stabilises mast cell membranes, prevents release of inflammatory mediators
what prevents the effects of mast cell activation
anti-histamines, leukotriene receptor antagonist
how do anti-histamines work
anti-histamines- block biological effects of histamines , used prophylactically (preventative) and to control symptoms (e.g. loratadine and cetirizine)
how do leukotriene receptor antagonists work
block effects of leukotrienes which are synthesised by mast cells after activation (e.g. montelukast)
name and describe the anti-inflammatory agents used to treat IgE mediated disorders
corticosteriods, inhibits formation of many different inflammatory mediators
how is anaphylaxis treated
self-injectable adrenalin- acts on beta2 adrenergic receptors to constrict atrial smooth muscle
what does the constriction of arterial smooth muscle because of adrenalin result in
increased blood pressure, limited vascular leakage, dilation of bronchial smooth muscle, decreasing airflow obstruction
describe immunotherapy
controlled exposure to increasing amounts of allergen- gradually increasing dose of subcutaneous injection
summarise the ways in which IgE mediated allergic disorders are managed
avoidance of allergen, block mast cell activation, prevent effects of mast cell activation, anaphylaxis management, immunotherapy
what cam mast cells with IgE antobodies lead to, especially in asthma
activation of eosinophils
what is the atopic trait that is inherited and found in people who suffer unduly from allergy
raised levels of IgE
what can mast cell degranulation be triggered by
tissue injury, complement activation and by some bacteria independently of IgE, IgE
which allergens which lead to built in immune response now useless are one of the most powerful
worm allergens
classify type II hypersensitivity reactions
direct cell killing (cell bound antigen)
what does an antibody bind to
cell-surface antigens
what does antigen binding result in
activation of complement (cell lysis (rupture)) and opsonisation (antibody-mediated phagocytosis)
what does the heavy chain region of the antibody trigger
immune response
what antigen initiates the classical activation pathway of complement
IgM
how does IgM initiate complement
engages multiple antigens on surface of cell which causes conformational change in FC region of antibody
what do phagocytes express on their surface to bond to the heavy chain
Fc receptors for IgG
what part of antibody neutralises
antigen binding portion
what are the functions of antibodies (6)
activates complement, activates antigens dependant cellular activity (e.g. NK cells/ eosinophils), acts on opsonins, activates T lymphocytes, causes antigen clumping and inactivation of bacteria complexes, triggers mast cell degranulation
describe complement
20 tightly regulated, linked proteins produced by liver in response to inflammation
what happens when complement is activated
enzymatically activate other proteins in a biological cascade
what antibody is best for parasitic infection
IgE
for normal antigens what antibody is the best
IgG
what does IgG trigger
classical pathways and cleavage of C3 into C3a and C3b, and then goes downstream into many different functions
what are the three pathways that lead ti activation of complement (C3)
classical- antigen + antibody + C1 complex
Lectin- MBL + mannose(+ve) pathogen
alternative- spontaneous C3 cleavage
what does the cleavage of C3 lead to
chemotaxis, solubilzation, direct killing (membrane attack complex), opsonisation
what does membrane attack complex do
punches holes in bacterial cell membranes, can directly kill encapsulated bacteria
what molecules involved in chemotaxis increase permeability of blood vessels
C3a and C5a fragments
why in chemotaxis is permeability of blood vessels increased
to increase traffic to cells of sites of infection
what do opsonins act as a bridge between
the pathogen and phagocyte receptors
what fragment of C3 is an opsonin
C3b
how is complement regulated via negative feedback
as fragments of complement can dissolve the immune complexes which triggered them- switching off complement activation
what is solubilzation
complement proteins breaking down large antibody complexes so they can be phagocytosed
give a clinical example of type II hypersensitivity
immune haemolytic amaemias
what type of hypersensitivity reaction is ALLERGIC haemolytic anaemia
type I
what happens in an acute haemolytic transfusion reaction
ABO incompatibility = lysis of donor erythrocytes by pre-formed IgG antibodies
what are the symptoms of a transfusion reaction
increased resp rate, tachycardia, kidney problems, decreased O2 sats
what type of antibodies are in type A blood
anti B
what type of antibodies are in type B blood
anti A
what type of antibodies are in type AB blood
neither A/B
what type of antibodies are in type O blood
both anti A & B
describe penicillin induced immune haemolytic anaemia
penicillin too small to induce antibodies, binds to surface protein of red blood cells, now has very antigenic structure, drives B cell response which leads to production of IgG antibodies and immune response (antibody bond to FcR om specific macrophage)
how is a transfusion reaction treated
plasmapheresis- removal of pathogenic antibodies from serum in the blood via cell separator
immunosupression-switch off B cell production
classify type III hypersensitivity reactions
immune complex needed
what is the key component of a type III reaction
antibody to soluble antigens
describe the pathophysiology of type III reactions
in presence of excess antigen, antibody binds forming small immune complexes which are trapped in small blood vessels, joints and glomeruli (filtration unit of kidney)
what do the signs and symptoms of type III reactions depend on
the tissue in which the immune complex is deposited in
what does the presence of an immune complex in type III reactions cause
activation of complement and attracts inflammatory cells (neutrophils). Neutrophils cannot phagocytose complex due to size so degranulate releasing enzymes causing bystander tissue damage
why do mould particles cause type III reactions
as when inhaled stimulate antibody formation- antibodies form immune complexes with antigen; results in complement activation, inflammation, recruitment of other leukocytes
give examples of acute hypersensitivity pneumonitis
farmers lung, bird fanciers lung, cheese workers lung, malt workers lung
what is ACUTE hypersensitivity pneumonitis mediated by
type III hypersensitivity response- when immune complexes deposited in walls of alveoli and bronchioles- CHRONIC DIFFERENT
what are the symptoms of acute hypersensitivity pneumonitis
wheeze, breathlessness, malaise and pyrexia
explain wheezing in A.H.P
bronchoconstriction- inflammation of the terminal bronchioles and alveoli caused by activated phagocytes and complement
explain breathlessness in A.H.P
alveolitis, inflammation of air sacs, caused by activated phagocytes and complement
explain malaise and pyrexia in A.H.P
systemic manifestation of inflammatory response
how are type III hypersensitivity reactions managed
avoidance, corticoidsteriods (decrease inflammation), immunosuppression (decrease production of IgG)
what type of drug are corticosteroids
glucocorticoids
classify type IV hypersensitivity reactions
delayed type hypersensitivity
what are type IV hypersensitivity reactions driven by
CD4 + t cells
what disease are associated with type IV hypersensitivity reactions
autoimmune- type 1 diabetes, psoriasis, rheumatoid arthritis
non-autoimmune- contact dermatitis, TB, leprosy, sarcoidosis, cellular rejection of organ transplant
what initially happens in a type IV reaction
generation of primed effector TH1 cells and memory T cells
what happens after subsequent exposure to pathogen in a IV response
activation of previously primed t cells, recruitment of macrophages, other lymphocytes, neutrophils… release of proteolytic enzymes, presistent inflammation- tissue damage
when does subsequent exposure in IV reactions happen
in autoimmunity, constant exposure to antibody or antigen stimulates macrophages which drives an ongoing response
give an example of type IV hypersensitivity reaction
poison ivy
what is chemokines role in type IV reactions
macrophage recruitment to site of antigen
what is INF-gamma role in type IV reactions
activates macrophages, increasing release of inflammatory mediators
what is INF-alpha and leukotriene role in type IV reactions
local tissue destruction, increased expression of adhesion molecules on local blood vessels
what are granulomas and their role
collection of walled off macrophages and T helper 1 cells to encase inflammatory reaction and limit tissue damage
e.g of type IV hypersensitivity- sarcoidosis, describe
multisystem granulomatous disease, characterised by granulomas, patches of red and swollen tissue
describe the immune process of sarcoidosis
antigen inhaled, stimulation of alveolar macrophages and CD4 and CD8 t cells, and B cells. Failure to clear antigen results in persistent inflammation and granuloma formation= tissue damage and fibrosis
how is sarcoidosis managed
systemic corticosteroids- block t cell and macrophage activation
what is the ABCD of hypersensitivity reactions
I= Aleergic Anaphylaxis Atropy II= antiBody III= immune Complex IV= Delayed
describe the onset of type 1 reactions
seconds if IgE preformed
describe the onset of type 2 reactions
seconds if IgG/M preformed
describe the onset of type 3 reactions
hours if IgG preformed
describe the onset of type 4 reactions
2-3 days
describe the infectious trigger of type 1 reactions
parasites
describe the infectious trigger of type 2 reactions
none
describe the infectious trigger of type 3 reactions
post streptococcal glomeruonephritis
describe the infectious trigger of type 4 reactions
Hep B virus
describe the environmental trigger of type 1 reactions
allergens
describe the environmental trigger of type 2 reactions
immune haemolytic anaemias
describe the environmental trigger of type 3 reactions
farmers lung
describe the environmental trigger of type 4 reactions
contact dermatitis, sarcoidosis
describe the adaptive immune mediators of type 1 reactions
TH2 cells, B cells, IgE
describe the adaptive immune mediators of type 2 reactions
B cells, IgG/M
describe the adaptive immune mediators of type 3 reactions
B cells IgG
describe the adaptive immune mediators of type 4 reactions
Th1 cells
describe the innate immune mediators of type 1 reactions
mast cells, eosinophils
describe the innate immune mediators of type 2 reactions
complement, phagocytes
describe the innate immune mediators of type 3 reactions
complement, neutrophils
describe the innate immune mediators of type 4 reactions
macrophages
what is the major hallmark of immune deficiency
recurrent infections; serious, persistent, unusual- SPUR
what other features suggest a immunodeficiency
weight loss, skin rash, diarrhoea, mouth ulcers
what are the classifications of immunodeficiencies
primary (gentically encoded), secondary (acquired throughout life)
what conditions are associated with secondary immune deficiency
infection, treatments, malignancy, biochemical and nutritional disorders, physiological immune deficiency
what cause physiological secondary immune deficiencies
old age/ prematurity
how can chemotherapy cause immune deficiency
as kills rapidly dividing cells- bone marrow heamatic stem cells
what is the purpose of PAMPs
to recognise structures that are unique to infectious organisms
what cells make up the innate immune system
macrophages, neutrophils, mast cells, natural killer cells
what proteins make up the innate immune system
complement, acute phase proteins, cytokines
what is tnf alpha
pro inflammatory mediator
what proteins and cells make up the acquired immune response
B and T lymphocytes, proteins - antibodies
name two phagocytes
macrophages and neutrophils
what are clinical features of phagocyte deficiencies
recurrent infections of common and unusual sites
what produces chemokine signals that initiate chemotaxis
pathogen or chemotactic signals from infected tissue
what is recticular dysgenesis, how is it treated and what happens is it is not
immunodeficiency where production of immune cells is blocked, bone marrow transplant, die shortly after birth
what is kotsmann syndrome and what causes it
blocked neutrophil development and maturation due to mutation in receptor or cytokine
what is a SCID
severe combines immunodeficiencies
what are SCID genetically and phenotypically
heterogeneous diseases
describe kostmann syndrome genetically
rare autosomal recessive
what is neutropenia
low levels of neutrophils in the blood
what will affect the treatment of kostmann syndrome
whether the mutation is in the cytokine or the ligand
how is kostmann syndrome treated
supportive treatments for the infections, definitive treatments (stem cell transplant and granulocyte colony stimulating factor
what would you expect in someone whose phagocytes were unable to bind to endothelial adhesion molecules
recurrent infections, v high neutrophil blood count, no pus formation in infected sites
why would there be an increased neutrophil blood level if phagocytes couldn’t bind to endothelial adhesion molecules
as cant migrate from vessels and cytokines would send signals to bone marrow to produce more
describe leukocyte adhesion deficiency and how it is acquired
failure of mobilised neutrophils to recognise activation markers expressed on endothelial cells so can exit bloodstream- genetically inherited
describe direct recognition of pathogens by phagocytes
done by pathogen recognition receptors that recognises microbial specific structures
describe indirect recognition of pathogens by phagocytes
opsonins (e.g. antibody or complement fragment) act as binding enhancers for the process of phagocytosis and bind to phagocyte when also bound to pathogen
what can cause a defect in pathogen recognition cause
defect in opsonin receptors (Fc or CR1)
what investigations would be undertaken to determine whether a patient has an immunodeficiency
blood count- neutrophil numbers, serum immunoglobulins, IgE, complement
what is chronic granulomatous disease
failure of oxidative killing mechanisms- deficiency in intracellular killing mechanisms of phagocytes
what does failure of oxidative killing mechanisms result in
inability to generate oxygen free radicals- impaired intracellular killing of micro-organisms
what is the presentation of a failure of oxidative killing mechanisms
inability to clear organisms- excessive inflammation (cant degrade and immune cells build up) and granuloma formation
what are the clinical features of chronic granulomatous disease
recurrent deep bacterial infections, recurrent fungal infections, failure to thrive, lymphadenopathy, granuloma formation
how is chronic granulmatous disease investigated
NBT test to show whether neutrophils can kill through production of oxidative free radicals
how is chronic granulomatous treated
supportive treatment (prophylactic antibiotics/fungals) definitive treatment- stem cell transplant and gene therapy
how does mycobacteria avoid the immune system
by hiding within immune cells- macrophages
how does the body defend against intracellular organisms such as mycobacteria (TB)
activate IL-12- IFN gamma network ( infected macrophages stimulated to produce IL-12 which induces TH1 cells to secrete IFNgamma which stimulates production of TNF which stimulates oxidative pathways)
what are defects in the IL-12; INFgamma axis associated with
susceptibility to intracellular bacteria- e.g mycobacterial infection (TB) and salmonella
how is phagocyte function investigated
blood count, presence of pus, expression of neutrophils adhesion mols (Phagocyte recruitment) chemotactic and phagocytosis assays find and kill the bug) NBT test (oxidative killing)
describe neutrophil count, pus formation, leukocyte adhesion markers and NBT test in congenital neutropaenia
NC-absent
PF-No
LAM-normal
NBT-absent (no neutrophils)
describe neutrophil count, pus formation, leukocyte adhesion markers and NBT test in leukocyte adhesion defect
NC-increased during infection
PF-no
LAM-absent
NBT- normal
describe neutrophil count, pus formation, leukocyte adhesion markers and NBT test in chronic granulomatous disease
NC-normal
PF-yes
LAM-normal
NBT-abnormal
what does failure of neutrophil differentiation cause
severe congential neutropaenia and cyclic neutropaenia (recurrent)
name the organs involved in the acquired immune system
lymphatics, bone marrow, intestines, spleen, kidney, appendix, thymus, heart
where does proliferation and maturation of T lymphocytes happen
in the thymus
what are the function of CD4 + T lymphocytes
immunoregulators and recognise peptides presented on MHC class 2 molecules
what is the role of CD8+ T lymphocytes
cytotoxic cells- recognise peptides in association with MHC class 1 molecules and kill cells directly
what are CD8+ T lymphocytes most important in protecting the body form
viral infections and tumours
what is the function of B lymphocytes
antibody production and antigen presentation
where do B lymphocytes arise from
haemopoetic stem cells in bone marrow
where are mature B lymphocytes mainly found
bone marrow, lymphoid tissue, spleen
what causes B lymphocytes to activate
encounters with antigen within lymph nodes
what are 3 functions of antibodies
identification of pathogens, recruitment of other components of immune response (complement, pathogens, NK cells), neutralisation of toxins
what is recticular dysgenesis
defect of the haemopoetic stem cells
what is severe combined immunodeficiency a defect of
lymphoid precursor- failure of production of lymphocytes
what is the clinical phenotype of severe combined immunodeficiency
unwell by 3 months of age, persistent diarrhoea, infections, unusual skin disease, family history of early infant death
what is the most common form of severe combined immunodeficiency
X-linked SCID, mutation of a component of the IL-2 receptors
what is the clinical phenotype of x-linked SCID
very low or absent T cells (as IL2 important for T cell development), normal or increased B cells, poorly developed lymphoid tissue and thymus
how is SCID treated
prophylactic treatment for infections, definitive treatment- stem cell transplant, gene therapy (for ADA-SCID)
what is DiGeorge syndrome
developmental defect of the 3rd/4th pharyngeal pouch- cumulative effect of deletion of several genes
what is the clinical presentation of DiGeorge syndrome
hypocalcaemia, oesophageal atresia, T cell lymphopenia, congenital heart disease, facial deformities
what causes recurrent viral infections
CD8 + T cells absent (+other T cells)
what causes recurrent bacterial infections
lack of CD4 + TFH as help B cells make antibody
what causes recurrent fungal infections
lack of CD4 + TH cells
what will laboratory investigations show in a patient with DiGeorge Syndrome
absent or decreased T cells (as defective activation response), normal or increased B cells, low serum antibody levels, normal NK levels
how is DiGeorge syndrome managed
correct metabolic/ cardiac abnormalities, prophylactic antibiotics; T cell function improves with age
what part of T lymphocyte development does DiGeorge syndrome affect
export of mature T lymphocytes to periphery
what are disorders of T cell effector function
cytokine production, cytotoxicity, T-B cell communication
a deficiency in a component in what axis can lead to a deficiency of cytokine production by T cells
IL-12; IFN gamma network
in what form of SCID is normal T cells level present
bare lymphocyte syndrome
what does bare lymphocyte syndrome result in
failure of expression of MHC molecules
what does autoimmune lymphoproliferative syndrome result in
failure of abnormal apoptosis
what are the clinical features of T cell deficiencies
recurrent infection, autoimmune disease, malignancies at young age
what is affected when there is an immune deficiency affecting B lymphocytes
antibody deficiencies
what is the presentation of antibodies deficiencies
recurrent bacterial infections, antibody mediated autoimmune diseases
what is brutons x-linked hypogammaglobulinaemia
b cell maturation defect
what does common variable immune deficiency affect and result in
B cells- failure to produce IgG, failure of lymphocyte precursors,
what is common variable immune deficiency and its clinical features
heterogeneous group of disorders; reccurent bacterial infections, autoimmune and granulomatous disease
what is x-linked hyper IgM syndrome
failure of TFH cell co-stimulation
what is selective antibody deficiency
failure to produce specific antibodies
what are the clinical features of B cell deficiencies
recurrent infections, opportunistic infections, antibody mediated autoimmune disease
how are B cell deficiencies managed
treatment of infection, immunoglobulin replacement, stem cell transplantation
out of IgM, IgG and IgA what serum immunoglobulins will be normal in selective IgA deficiency
M and G, A absent or decreased
out of IgM, IgG and IgA what serum immunoglobulins will be normal in x linked agammaglobulinaemia
none
out of IgM, IgG and IgA what serum immunoglobulins will be normal in common variable immune deficiency
IgG, M and A decreased or absent
out of IgM, IgG and IgA what serum immunoglobulins will be normal in specific antibody deficiency
all
in which primary antibody deficiency are b lymphocyte sub populations decreased or absent
x linked agamma-globulinaemia
what other investigation can be used to investigate primary antibody deficiencies
failure to produce vaccine specific antibodies (happens in all except selective IgA deficiency
