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
Describe passive immunity and how it is acquired:
* 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
List the European Society for Immunodeficiencies warning signs for ADULT primary immunodeficiency diseases:
* 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
How do antibodies deficiencies present?
* 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
Name possible causes of secondary antibody deficiencies:
* **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
What basic tests would you like to do to identify possible secondary cause of antibody or other problems leading to recurrent infection?
_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
Routine testing for immunoglobulins:
* 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 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
Describe immunoglobulins by age:
32
What is X-linked agammaglobinaemia?
* 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
How does XLA manifest?
* 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
How do you treat XLA?
* 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
What is common variable immunodeficiency (CVID)?
* 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
List the CVID diagnostic criteria:
**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
How does CVID manifest?
* 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
What is the treatment for CVID?
* 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
What is specific antibody deficiency?
* 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
How do you treat SpAD?
* Prophylactic antibiotics in first instance
* Immunoglobulin replacement if ongoing recurrent infection
41
What is selective IgA deficiency?
* 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
T cell deficiency:
* 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
What is a classic presentation of SCID?
* \<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
List infections commonly seen in combined T & B cell deficiencies:
* 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
What investigations and findings would you find in SCID?
* 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
What is Omenn syndrome?
* type of SCID
* some T cells are produced but they are not properly activated and can be self-reactive
47
What is found in Omenn syndrome?
* 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
What genetic mutation is found in Omenn syndrome?
* 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
What is the pathogenesis of Omenn syndrome?
* 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
CD40 L or CD40 deficiency
* 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
How to diagnose CD40(L) deficiency?
* 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
DOCK 8 deficiency
* 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
Clinical manifestations of DOCK 8 deficiency:
* eczema
* recurrent resp infections
* severe (food) allergies
* viral infections
* abscesses
* candidiasis
* failure to thrive
Mx HSCT
54
Other things seen in combined immunodeficiencies:
* loss of 'self tolerance'
* central tolerance - thymic deletion
* peripheral tolerance - Tregs
55
Classic PID and what malignancies they are associated with:
* 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
Deficiencies of the innate immune system:
* phagocyte disorders:
* reduced numbers
* reduced function
* NK cell defects
* cytokine deficiencies
* toll-like receptor defects
* complement deficiency
57
Phagocyte (neutrophil) defects:
* 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
What goes wrong to cause chronic granulomatous disease?
* 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
What are the key features of chronic granulomatous disease?
* 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
How do you diagnose CGD?
* 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
How do you treat chronic granulomatous disease?
* 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
Examples of other neutrophil defects of killing:
* myeloperoxidase deficiency
* G6PD deficiency
* both present with similar presentations to CGD but milder forms
* confirm by measuring enzyme levels
63
Leukocyte adhesion deficiency:
* 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
Other neutrophil defects: chediak-higashi syndrome
* 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
Other defects of neutrophils: griscelli syndrome
* global pigmentary dilution with silvery grey hair
* abnormal management of intracellular granules
* pyogenic iinfeciotns
* HSCT can cure immunologic abnormalities
66
Name secondary causes of neutropenia
* infection
* immunosuppression
* malignancy
67
Name primary causes of neutropenia:
* 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
How to diagnose neutropenia:
* neutrophil count on FBC
* need to determine if persistent or cyclical drop every 21 days
69
Name the secondary cause of NK defects:
* meds, malignancy, infection
70
Name the primary causes of NK deficiency:
* reduced numbers/absent
* GATA2 (a haematopoietic transcription factor) deficiency
* reduced function/normal number
71
What are the key features of NK deficiency?
* patients present with exess of herpes viral infections
* e.g. VZV, CMV, EBV and HSV
* unusual features of HPV - excess malignancy
72
Describe type 1 cytokine defects:
* autosomal recessive
* increased susceptibility to mycobacterial disease
* patients with IL-12 deficiency also develop susceptible to salmonellosis
73
Diagnosis of type 1 cytokine defects:
* measurement of cytokine levels (specialist tests)
* IFN-gamma levels low in IL-12 deficiency
* raised in IFN-gamma receptor deficiency
74
What is the treatment of type 1 cytokine deficiency?
* antimycobacterial regimens
* prophylaxis
* IFN-gamma
* HSCT
75
Toll-like receptor function defects:
* 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
Complement deficiencies:
* increased susceptibility to infection
* increased susceptibility to autoimmunity
* hereditary angioedema
77
