Immunology Flashcards
1
Q
Describe the main features of the innate immune system.
A
- Pre-existing defences
- First-line defence
- Responds to broad types of threats, rather than specific pathogens
- No change in response with repeated exposure
2
Q
Describe the main features of the adaptive immune system.
A
- Recognises and responds to specific threats (specificity)
- Mounts a highly tailored response against specific threat
- Takes time to develop
- stronger/faster response with repeated exposure (immunological memory)
3
Q
List the initial defences of the innate immune system:
A
- physical barriers
- skin
- mucous membranes
- chemical barriers
- acidic pH in GI tract and on skin
- enzymes (lysozyme) in tears and saliva
4
Q
Name the three phagocytic cells of the innate immune system:
A
- neutrophils
- monocytes
- macrophages
5
Q
What is the roll of neutrophils?
A
- short lived cells
- recruited to sites of inflammation
- phagocytosis
- contain numerous granules rich in degradative enzymes and anti-microbial substances
6
Q
What are the roles of eosinophils and basophils?
A
- defence against parasites
- allergic inflammatory reactions
- also contains granules rich in degradative enzymes and anti-microbial substances (they are granulocytes)
7
Q
What are monocytes?
A
- myeloid derived cells, leave bone marrow
- circulate in blood
- phagocytic
- migrate into tissues where they differentiate
8
Q
What are macrophages?
A
- monocyte derived tissue-based cells (monocytes differentiate into macrophages when they move into tissues)
- phagocytes
- secrete cytokine
- link to adaptive immune response as they are APCs
9
Q
What is a dendritic cell?
A
- widespread in various subsets
- phagocytic –> type of APC (link to adaptive immune system)
- also ingests extracellular fluid to find non-self antigens and present them to the adaptive immune system
10
Q
what is a natural killer cell?
A
- type of ‘large granular’ lymphocyte
- kill infected cells and tumour cells (recognise lack of normal ‘self’
11
Q
What is an epitope?
A
- the particular part of the antigen recognised bu the innate or adaptive immune system receptor
12
Q
What are antigen presenting cells?
A
- APCs are cells that express the MHC class II - part of the cell that has been phagocysed is joined to the MHC class II protein and then this complex is expressed on the surface of the cell
- the main APCs that link the adaptive to the innate immune system are:
- dendritic cells
- macrophages
13
Q
What are the two arms of the adaptive immune system?
A
- cell mediated: CD4+and CD8+ T lymphocytes
- humoral: B lymphocytes and antibodies
14
Q
Describe the structure of an antibody?
A
15
Q
Describe the structure of a T cell receptor, that is found on the surface of a T cell:
A
- each T cell expresses a TCR of a single specificity
- TCRs recognise antigen expressed on cell surface in conjunction with MHC molcules
16
Q
What are CD4 and CD8 co-receptors?
A
- on the surface f T cells
- Determine if T cells bind to MHC class I or II molecules
17
Q
What is the role of CD4+ cells?
A
- recognise antigen expressed on cell sirface in conjunction with MHC class II (only present on specialised APCs)
- results in T cell activation under appropriate circumstances, and division to form ‘effector cells’
- also known as helper T cells
- after activation:
- multiply and form multiple daughter cells that migrate to site of inflammation/infection via the bloodstream
- produce cytokines that direct the immune response
*
18
Q
What is the role of CD8+ T cells?
A
- kill infected cells (cytotoxic T cells)
- recognise antigen expressed on the surface in conjunction with MHC class I (expressed by all cells - this is how a cell will flag itself to the immune system as being infected by e.g. a virus)
19
Q
What is the role of a B cell?
A
- Express B cell receptor, which is basically a membrane bound antibody
- BCR comes into contact with antigen that matches > internalised, broken down and presented via MHC class II > binds with CD4 T helper cell > helper t cell activates B cell, causing it to produce more of the antibody and secrete it
20
Q
What is the role of peripheral (secondary) lymphpid tissue?
A
- where adaptive immune response are initiated
- lymph nodes
- spleen
- mucosal associated lymphoid tissue (area in GI tract)
- faciliates antigen and lymphocytes to come together, allowing adaptive immune responses
- dendritic cells expressing antigen migrate from tissues to secondary lymphoid organs
- naive lymphocytes circulate through lymph nodes via the blood stream
21
Q
Give an outline of the circulation of lymph:
A
- Lymph is essentially extracellular fluid from all tissue, but contains APCs bringing antigen from tissue
- Drains in a series of afferent lymphatic vessels into secondary lymphoid tissues
- Fluid (lymph) then leaves lymph nodes via efferent lymphatic vessels, which drain into a collecting lymphatic vessel called the thoracic duct
- This then drains into the bloodstream via the heart
22
Q
What is the purpose of the lymphatic system?
A
- allows peripheral fluid to drain back towards the secondary lymphoid organs
- brings APCs into contact with the adaptive immune system where it can be activated
23
Q
Describe the journet of lymphocytes through the lymphatic system:
- naïve lymphocytes enter the lymph nodes from the bloodstream
- there they sample the environment for antigen presented by APCs
- if they encounter their antigen and are activated, they divide to form ‘effector’ cells
- effector lymphocytes (or naïve cells that have not encountered their antigen) leave lymph nodes via efferent lymphatics
- drain into thoracic duct and back into bloodstream
- activated ‘effector’ cells then home to inflamed tissues (e.g. sites of infection)
- naïve cells home back to lymph nodes again and continue to circulate between lymph nodes and blood until antigen encountered
A
- naïve lymphocytes enter the lymph nodes from the bloodstream
- there they sample the environment for antigen presented by APCs
- if they encounter their antigen and are activated, they divide to form ‘effector’ cells
- effector lymphocytes (or naïve cells that have not encountered their antigen) leave lymph nodes via efferent lymphatics
- drain into thoracic duct and back into bloodstream
- activated ‘effector’ cells then home to inflamed tissues (e.g. sites of infection)
- naïve cells home back to lymph nodes again and continue to circulate between lymph nodes and blood until antigen encountered
24
Q
Describe active immunity and how it is acquired:
A
- protection that is produced by an individual’s own immune system and is usually long-lasting
- acquire by natural disease or vaccination
- involves generation of adaptive immune responses, resulting in immunological memory
- includes antibody responses (B cells) and cell mediated responses (T cells), usually in combination
25
Q
Describe passive immunity and how it is acquired:
A
- protection provided by transfer of antibodies from immune individuals
- commonest examples if cross-placental transfer of antibodies from mother to child
- also used therapeutically through transfusion of blood or blood products including immunoglobulins
- gives temporary protection, only a few weeks or months
- related to half-life of antibodies
26
Q
List the European Society for Immunodeficiencies warning signs for ADULT primary immunodeficiency diseases:
A
- Four or more infections requiring antibiotics within one year (otitis, bronchitis, sinusitis, pneumonia)
- Recurring infections or infection requiring prolonged antibiotic therapy
- Two or more severe bacterial infections (osteomyelitis, meningitis, septicaemia, cellulitis)
- Two or more radiologically proven pneumonia within 3 years
- Infection with unusual localization or unusual pathogen
- PID in the family
Also remember Failure to Thrive in paediatrics
27
Q
How do antibodies deficiencies present?
A
- Recurrent bacterial infection
- Main sites are chest, sinuses (i.e. respiratory tract)
- Ear and eye infections also common
- Recurrent infection eventually causes end organ damage e.g. bronchiectasis
- Primarily encapsulated bacteria
- E.g Streptococcus pneumoniae (Pneumococcus), Haemophilus, Klebsiella, Pseudomonas etc.
- These have polysaccharide capsule that impairs phagocytosis by phagocytes (e.g. neutrophils and macrophages)
- Antibodies are produced against polysaccharide antigens in capsule
- Binding of antibodies results in ‘opsonisation’, greatly enhancing phagocytosis by phagocytes
- Viruses can usually be cleared, but difficulty forming protective immunity can lead to recurrence (e.g. recurrent shingles)
28
Q
Name possible causes of secondary antibody deficiencies:
A
- More common than primary
- Drugs [cytotoxics, anti-convulsants, anti-rheumatics, Rituximab]
- Radiation
- Malignancy [CLL, myeloma]
- Loss [gut, kidney]
- Nutrition [B12]
- Metabolic
- Infections (HIV, CMV, EBV, Toxoplasma)
- Extremes of age / immunosenescence
29
Q
What basic tests would you like to do to identify possible secondary cause of antibody or other problems leading to recurrent infection?
A
FBC
- Haemoglobin & indices
- Malabsorption, anaemia of chronic disease
- Evidence for marrow failure
- Thrombocytopenia
- White cell count
- Lymphopenia or lymphocytosis
- Neutropenia
- Blood film
- Abnormal cells [smear cells, blasts]
Biochemistry
- Liver function tests
- Albumin for renal or GI loss
- Thyroid function
- Creatinine & urea [renal disease]
- Blood glucose [HbA1c]
- Urinary protein excretion [Stick test first]
30
Q
Routine testing for immunoglobulins:
A
- Routine testing involves testing IgG, IgA and IgM (together constitute almost all serum immunogobulin)
- Normal range (adults)
- IgG 5.8 - 15.4 g/L
- IgA 0.64 - 2.97 g/L
- IgM 0.24 – 1.9 g/L (male), 0.71 – 1.9 (female)
- Age-specific ranges in children
- Normal range (adults)
- Normal levels do not exclude significant immunodeficiency
- If considering hyper-IgE syndrome also need to check total IgE [typically very raised often >50,000 kU/l]
31
Q
Describe immunoglobulins by age:
A
32
Q
What is X-linked agammaglobinaemia?
A
- Defect is loss of function mutation in BTK (Bruton’s tyrosine kinase)
- This is involved in signalling of pre B cell receptor and B cell receptor
- Absence causes block in maturation at pro-B cell stage
- No mature B cells form
- Classically leads to:
- Total absence of circulating B cells
- Absent immunoglobulins (IgG, IgA, IgM)
33
Q
How does XLA manifest?
A
- Presents in male children (X-linked), with infections usually starting in first year of life (when maternal IgG dwindles, so not at birth)
- Recurrent upper and lower respiratory tract infections
- Encapsulated bacteria, e.g. Strep pneumoniae, Haemophilus influenzae, Staph aureus, Pseudomonas
- Invariably develop bronchiectasis, especially if delayed diagnosis
- Other bacterial infections e.g. meningitis, osteomyelitis, septic arthritis
- Most viral infections can initially be cleared, but sensitive to enteroviruses, including polio live vaccine strain
34
Q
How do you treat XLA?
A
- Immunoglobulin replacement (subcutaneous or intravenous) is essential life-long
- Sometimes prophylactic antibiotics are also required
- Goal is to prevent end organ damage particularly bronchiectasis
- Severe refractory cases can treated curatively with haematopoietic stem cell transplant (HSCT)
- No live vaccines
35
Q
What is common variable immunodeficiency (CVID)?
A
- Relatively common as PIDs go, but still rare (approx. 1 in 25000)
- Variable, as in reality it is probably many different genetic defects, with broadly similar phenotype (many identified, many likely yet to be)
- Primarily antibody deficiency, particularly low IgG (and IgA)
- Can present from childhood (not infancy) until well into adulthood
- Diagnosis often delayed many years after first manifestations
36
Q
List the CVID diagnostic criteria:
A
At least one of:
- Increased susceptibility to infection
- Autoimmune manifestations
- Granulomatous disease
- Unexplained polyclonal lymphoproliferation
- Affected family member with Ab deficiency
AND
- Marked decreased in IgG and IgA (+/- IgM)
AND at least one of:
- Poor vaccine response (or absent isohaemaglutinins)
- Low class-switched memory B cells
AND
- Secondary causes excluded
AND
- Diagnosed after 4th year of life (although symptoms may have begun earlier)
AND
- No evidence of a profound T cell deficiency (2 or more of):
- CD4 numbers/microliter: 2-6y <300, 6-12y <250, >12y <200
- % naive of CD4: 2-6y <25%, 6- 16y <20%, >16y <10%
- T cell proliferation absent
37
Q
How does CVID manifest?
A
- Bacterial infections, as with XLA
- Autoimmune disease (e.g. haemolytic anaemias, cytopenias, thyroid disease and rheum arthritis)
- Enteropathy, Coeliac-like, Malabsorption
- Lymphoproliferation
- Sarcoid-like granulomatous disease, can affect any organ
- Granulomatous lymphocytic interstitial lung disease (GLILD) – serious manifestation from CVID that requires treatment with steroids
- Liver disease (nodular regenerative hyperplasia)
- Malignancy, especially lymphoma (40 fold increased risk)
38
Q
What is the treatment for CVID?
A
- Immunoglobulin replacement as with XLA
- Prophylactic antibiotics
- Treatment of complications, e.g. autoimmune disease as appropriate
- Some patients with active autoimmune disease or GLILD require immunosuppression, including steroids
- Monitoring for malignancy, particularly lymphoma
- Small (but increasing) numbers of complex patients treated with HSCT (curative but high mortality risk in adults, especially with comorbidity)
39
Q
What is specific antibody deficiency?
A
- It is possible to have normal total antibody levels, but fail to produce antibodies to certain types of antigens (particularly polysaccharide) – esp important in encapsulated bacteria
- This can be clinically significant, resulting in recurrent bacterial infections and risk of bronchiectasis
- By definition IgG, IgA and IgM levels are normal
- Specific bacterial antibodies, particularly to Strep pneumoniae (Pneumococcus) and Tetanus should be checked.
- If low, this does not necessarily mean a problem (may not have been vaccinated or significantly exposed
- Test vaccination given (e.g. PPV23), and levels repeated at 4-6 weeks
- Failure to adequately respond suggests SpAD
- Diagnostic criteria also required no evidence of T cell defect (combined immunodeficiency)
40
Q
How do you treat SpAD?
A
- Prophylactic antibiotics in first instance
- Immunoglobulin replacement if ongoing recurrent infection
41
Q
What is selective IgA deficiency?
A
- Selective IgA deficiency (absent IgA, IgG and IgM normal) is common (approx. 1/800), usually incidental finding (Coeliac screening – anti-TTG is an IgA so have to check the patient is not IgA deficient before using this test) and mostly not clinically relevant
- In absence of recurrent infection, no further investigation needed
- Rarely it can be associated with other antibody deficiencies (e.g. specific antibody deficiency) so if recurrent infections warrants investigation
42
Q
T cell deficiency:
A
- T cells required to clear viral and protozoal infection
- T cells required to clear intra- and extracellular bacterial infection
- Patients present with persistent viral infection, protozoal infection +/- bacterial infection
43
Q
What is a classic presentation of SCID?
A
- <12 months
- Persistent gut, resp viral infection
- Pneumocystis
- Maternal-foetal engraftment
- Absent thymopoiesis (not making T cells)
- absent or very low number of T cells
- very low T cell function
44
Q
List infections commonly seen in combined T & B cell deficiencies:
A
- bacterial
- intracellular (mycobacteria)
- Salmonella spp
- fungal
- Candida spp
- Aspergillus spp
- Cryptococcus neoformans
- protozoal
- Pneumocystis carinii
- Toxoplasma gondii
- Cryptosporidia
- Viral
- Respiratory: RSV, Parainfluenzae
- GI: rotavirus (vaccine strain), norovirus
- Other: CMV, adenovirus
45
Q
What investigations and findings would you find in SCID?
A
- Absolute lymphocyte count <2.5x109/L
- Lymphocyte subsets
- decreased CD3, CD4 & CD8 (decreased CD19)
- Lymphocyte proliferations
- Decreased PHA
- Igs
- Decreased (beware ‘low normal’ if first few weeks of life as maternal IgG present – in this case check IgM)
46
Q
What is Omenn syndrome?
A
- type of SCID
- some T cells are produced but they are not properly activated and can be self-reactive
47
Q
What is found in Omenn syndrome?
A
- T cell infiltration of skin, gut, liver, spleen
- clinically GvHD - autologous T cells
- clonal lymphocytes
- raised T cells
- absent B cells
- normal NK
- eosinophilia
- Agammaglobulinaemia (increased IgE)
- absent thymopoiesis
48
Q
What genetic mutation is found in Omenn syndrome?
A
- missense mutation in Rag-1 or Rag-2
- resulting in partial V(D)J recombination
- other gene mutations can also contribute to Omenn syndrome
49
Q
What is the pathogenesis of Omenn syndrome?
A
- abnormal thymic development (due to abnormal T cell production)
- aberrant clonal T cell expansion (abnormal production of T cells in one family)
- autoantibodies to antigen (as thymus not developed properly so cannot ‘educate’ T cells
- mismatch in T cell/Treg repertoire
- environmental trigger
50
Q
CD40 L or CD40 deficiency
A
- technically a combined deficiency as deficient in T cells, but also cannot activate B cells
- U/LRTI from infancy
- pneumocystis jirovecii pneumonia
- giardia lamblia or crytosporidium diarrhoea (chronic diarrhoea that can lead to ascending cholangitis and liver disease –> therefore increased risk of HCC)
- sclerosing cholangitis associatde with crypto infection
- neutropenia with persistent stomatitis and mouth ulcers
- HCC
51
Q
How to diagnose CD40(L) deficiency?
A
- raised IgM, low/absent IgA & IgG - therefore also known as hyper IgM syndrome
- normal CD19 (normal number of B cells, but they just aren’t being activated to switch to making IgA and IgG)
- lack of CSM B cells
- reduced/absent CD40L expression
- genetic confirmation
52
Q
DOCK 8 deficiency
A
- dedicator of cytokinesis 8
- expressed in placenta, pancreas, lungs and lymphocytes
- important in lymphocytes for: migration, polarisation, phagocytosis, cell fusion
- AR hyper IgE syndrome is cuased by muttions in the DOCK8 gene
53
Q
Clinical manifestations of DOCK 8 deficiency:
A
- eczema
- recurrent resp infections
- severe (food) allergies
- viral infections
- abscesses
- candidiasis
- failure to thrive
Mx HSCT
54
Q
Other things seen in combined immunodeficiencies:
A
- loss of ‘self tolerance’
- central tolerance - thymic deletion
- peripheral tolerance - Tregs
55
Q
Classic PID and what malignancies they are associated with:
A
- severe combined immunodeficiency - lymphoma
- Wiskott-Aldrich syndrome - lymphoma
- CD40 ligand deficiency - HCC
- DOCK 8 deficiency
- X-linked lymphoproliferative disease - lymphoma
- DNA repair defects - lymphoma
- common variable immunodeficiency - lymphoma
56
Q
Deficiencies of the innate immune system:
A
- phagocyte disorders:
- reduced numbers
- reduced function
- NK cell defects
- cytokine deficiencies
- toll-like receptor defects
- complement deficiency
57
Q
Phagocyte (neutrophil) defects:
A
- defects in neutrophils (function or number)
- account for nearly 20% PIDs
- include chronic granulomatous disease, leukocyte adhesion deficiency, Chediak-Higashi, Griscelli syndrome, neutrophil. granule deficiency, severe congenital neutropenia (Kostmann syndrome) and X-linked neutropenia
58
Q
What goes wrong to cause chronic granulomatous disease?
A
- defect in NADPH oxidase complex resulting in inability to produce respiratory burst (and generation of oxygen free radicals would normally kill the microbe)
- several components of NADPH complex encoded by different genes
- you can get X-linked and AR forms
- failure to kill micro-organism leads to granuloma formation
59
Q
What are the key features of chronic granulomatous disease?
A
- early presentation - usually
- abscess and deep-seated infections of lungs, lymph nodes, liver (few diseases present with liver abscesses so important to consider CGD) and bones
- catalase positive bacteria - staphlococcus, klebsiella, serratia & burkholderia
- fungal infections - Aspergillus
- inflammatory bowel disease
60
Q
How do you diagnose CGD?
A
- determine phagocyte oxidase activity by measuring reduction of a fluorescent dye such as dihydrodamine (DHR)
- DHR reduction will produce a quantitive chaneg in fluorescence that can be measured by flow cytometry
- Request: neutrophil oxidative burst
- alternative diagnostic test:
- nitro blue tetrazolium (NBT) test
Other things to look for:
- culture for bacteria and fungi
- evidence of gut inflammation
- evidence of obstruction e.g. urethra secondary to granuloma
- total number of neutrophils are normal on FBC
61
Q
How do you treat chronic granulomatous disease?
A
- prophylactic antibiotics
- prophylactic anti-fungals
- ideally diagnosis is made at a very young age so that these can be started before complications of persistent infection –> if family history it is very important to screen at burth
- interferon gamma
- bona marrow transplant (mainstay of curative therapy)
- ? role for gene therapy
62
Q
Examples of other neutrophil defects of killing:
A
- myeloperoxidase deficiency
- G6PD deficiency
- both present with similar presentations to CGD but milder forms
- confirm by measuring enzyme levels
63
Q
Leukocyte adhesion deficiency:
A
- rare
- normal number of leukocytes
- normal oxidative burst but:
- inability of leukocytes to localise to sites of inflammation due to defective adherence mechanisms
- three types
- clinical manifestations vary but all have a defect in CD18 present on surface of leukocytes
- complete deficiency of CD18 results in death early in life but those with partial defects benefit from prophy;actic and acute antibiotics
- BMT may be required (curative)
64
Q
Other neutrophil defects: chediak-higashi syndrome
A
- abnormal neutrophil granules and defective killing
- occulocutaneous albinism, neurological symptoms and increased pyogenic infections
- can develop unchecked inflammation
- HSCT can cure immunological defects but not neurological symptoms
65
Q
Other defects of neutrophils: griscelli syndrome
A
- global pigmentary dilution with silvery grey hair
- abnormal management of intracellular granules
- pyogenic iinfeciotns
- HSCT can cure immunologic abnormalities
66
Q
Name secondary causes of neutropenia
A
- infection
- immunosuppression
- malignancy
67
Q
Name primary causes of neutropenia:
A
- severe congenital, cyclic or X-linked
- presents as:
- septicaemia, bacterial resp infections, soft tissue infections, gingivostomatitis, periodontitis and oral/vaginal/rectal ulcerations
- severity parallels the deficiency
68
Q
How to diagnose neutropenia:
A
- neutrophil count on FBC
- need to determine if persistent or cyclical drop every 21 days
69
Q
Name the secondary cause of NK defects:
A
- meds, malignancy, infection
70
Q
Name the primary causes of NK deficiency:
A
- reduced numbers/absent
- GATA2 (a haematopoietic transcription factor) deficiency
- reduced function/normal number
71
Q
What are the key features of NK deficiency?
A
- patients present with exess of herpes viral infections
- e.g. VZV, CMV, EBV and HSV
- unusual features of HPV - excess malignancy
72
Q
Describe type 1 cytokine defects:
A
- autosomal recessive
- increased susceptibility to mycobacterial disease
- patients with IL-12 deficiency also develop susceptible to salmonellosis
73
Q
Diagnosis of type 1 cytokine defects:
A
- measurement of cytokine levels (specialist tests)
- IFN-gamma levels low in IL-12 deficiency
- raised in IFN-gamma receptor deficiency
74
Q
What is the treatment of type 1 cytokine deficiency?
A
- antimycobacterial regimens
- prophylaxis
- IFN-gamma
- HSCT
75
Q
Toll-like receptor function defects:
A
- TLRs
- = pattern recognition receptors for lots of molecules (self and non-self) that contain danger signals
- key initiators of innate immune response
- if IRAK-4 and MyD88 pathway affected - patients susceptible to pyogenic organisms
- investigations (specialised)
- measure production of cytokines after exposure to peripheral blood mononuclear cells to TLR ligands
76
Q
Complement deficiencies:
A
- increased susceptibility to infection
- increased susceptibility to autoimmunity
- hereditary angioedema
77
Q
A
