Immunology Flashcards
What are the different types of allograft?
Solid organs: kidney, liver, heart, lung, pancreas
Small bowel
Free celss: bone marrow stem cells, pancreas isles
Temporary: blood, skin
Privileged sites: cornea
Framework: bone, cartilage, tendons, nerves
Composite: hands, face
Def: Allograft
Allotransplant (allo- from theGreek meaning “other”) is thetransplantation of cells, tissues, or organs, to a recipient from a genetically non-identical donor of the same species.[1] The transplant is called an allograft, allogeneic transplant, or homograft.
What are te main causes of renal allograft loss?
Infection
Rejection
Obstruction of the uretur
Vascular problems
Recurrent disease in the graft
What are the 3 stages of transplant rejection
Phase 1: recognition of foreign antigens
Phase 2: activation of Ag-specific lymphocytes
Phase 3: effector phase of graft rejection
What are the most relevant protein variations in clinical transplantation that lead to recognition of allograft as foreign?
ABO
HLA (coded on chromosome 6 by MHC)
(minor histocompatibility genes are some other determinants)
What are the 2 major components to rejection
T cell rejection
Ab-mediated rejection: B-cells
What is ABO?
A and B glycoproteins on BCs but also on endothelial lining of BVs in transplanted organ.
There are naturally occuring anti-A and anti-B Abs
What is the A antigen?
N-acetyl-glucosamine
What is the B antigen?
Galactose
AB antigen?
Has both N-acetyl-galactosamine and galactose on glycoproteins
Complete the table
What are HLA?
Cell surface protines
Involved in presentation of forgeign Ags to T-cells
Where are HLA Class I found?
A, B, C expressed on all cells
Where are HLA Class II found?
DR, DQ, DP
Expressed on APC but also upregulated on other cells during stress
What is the importance of HLA in infections/neoplasia vs transplantation?
Maximise diversity in defence against infections, each individual has a variety of HLA, which are derived from a large pool of population varieties.
Variability in HLA molecules in the population provides a source for immnisation against the transplanted organ
Complete the table
HLA MM Parent to child
Sibling to sibling
How many HLA loci?
>3/6 MM
25% 6MM
50% 3MM
25% 0MM
6
HLA Ags in transplantation
Exposure to foreing HLA molecules results in immune reaction to foreign epitopes, this causes damage to the graft-> rejection
T cell mediated rejection in transplantation
Require presentation of foreign HLA by APC, in context of HLA to initiate activation of alloreactive T-cells
What is the difference between the direct and indirect pathways in allograft rejection?
Direct: Donor APC presenting Ag and or MHC to recipient T cells. Acute rejection mainly involves direct rejection.
Indirect: recipient APC presenting donow antigenn to recipient T cells, mainly chronic rejection
T cell vs B cell recognition
T cells recognise Ag with MHC, B cell can recognise just Ag
T cell activation leads to:
Proliferation
Cytokines
Activation of CD8+
Ab production
Recruite phagocytes
Leads to Type IV hypersensitivity
What are the effector cells in T-cell mediated allograft rejection?
Cytotoxic CD8
CD4
Macrophages
What do CD4 cells do in allograft rejection in what phase?
Graft infiltration by alloreactive CD4 cells
Phase 3
What do cytotoxic T cells do in allograft rejection and in what phase?
Release toxins to kill target: Granzyme B
Punch holes in target: perforn
Apoptotic cell death: Fas-L
Phase 3
What do macrophages do in allograft rejection and in what phase?
Phagocytose
Release proteolytic enzymes
Produce cytokines
Produce O radicals and N radicals
What are the symptoms of acte T cell mediated rejection
Deteriorating graft function e.g. RFTs, LFTs, pulmonary oedema dependant on graft type
Pain and tenderness over graft
Fever
A 55 year old man is day14 post deceased donor kidney transplantation. After initial good kidney function with a creatinine falling to 100 umol/L, a routine follow-up finds a creatinine of 145 umol/L
What do you do?
- Ultrasound examination of the graft
- Biopsy of the graft
- Urine analysis
- Surgical exploration of the graft
- Treat blind with corticosteroids
Graft biopsy
What may you see in a graft biopsy of acute cellular rejection of an allograft
Inflammation e.g. tubulitis, arteritis
What occurs in Phase 3 of allograft rejection leading to inflammation?
Abs bind to graft endothelium e.g. capillaries of glomerulus and around tubules, arterial in kidney for e.g.
Net result is vasculopathy
What is the difference between AB Abs and anti-HLA Abs
What can anti-HLA Abs be?
Anti-A/Anti-B are naturally occuring
Anti-HLA Abs are not naturally occuring
Preformed: previous exposure to epitopes e.g. previous transplantation, pregnancy, transfusion
Post-formed: arise post-transplantation
What are the features of chornic rejection of the liver?
Fibrosis
What are the features of chornic rejection of the kidney?
Fibrosis
Glomerulopathy
Capillary BM membrane changes
What are the features of chornic rejection of the pancreas
Fibrosi
Vasculopathy
What are the features of chornic rejection of the lung
Bronchiolitis obliterans
What are the features of chornic rejection of the heart?
Vasculopathy?
What are the types of rejection?
What is thus important?
- T-cell mediated, antibody-mediated or combined
- Importance of graft biopsy for diagnosis as management and outcome are different
How can you prevent rejection?
Treat?
What is important to consider?
AB/HLA matching
Screening for anti-HLA Abs
Immunosuppression
More immunosuppressoin
Balance the need for immunosuppression with the risk of infection/malignancy/ toxicity
When does the screening for Abs in transplantation occur?
Before
At time
After
What are the 3 main types of anti-HLA Ab screening assays?
Cytotoxicity
Flow cytometry
Solid phase
What is the principle for cytotoxicity assay in transplantation?
Does the recipient serum kill the donor’s lymphocytes in the presence of complement
What is the principle for flow cytometry in transplantation?
Does the recipient’s serum bind to the donor’s lymphocytes?
What is the principle for solid phase assays in the context of transplantation?
Does the recipient’s serum bind to recombinant single HLA molecules attached to solid supports such as beads?
Modern transplant immunosuppression outline:
Induction agent: ex. AKT3/ATG, anti-CD52 (alemtuzumab), anti-CD25 (Basiliximab)
Base-line immunosuppression: Calcineurin Inhibitor + mycophenolate mofetil (MMF) or Azathioprine +/- steroids
Treatment of acute rejection: cellular
Steroids. ATG/OKT3
Treatment of acute rejection: Ab-mediated
IVIG, anti-CD5, anti-CD20
PLEX
What is GvHD?
- Eliminate hosts immune system (total body irradiation; cyclophophamide; other drugs)
- Replace with own (autologous) or HLA-matched donor (allogeneic) bone marrow
- Allogeneic HSCT leads to reaction of donor lymphocytes against host tissues
- Related to degree of HLA-incompatibility
Also Gv Tumour effect
What is used for GvHD prophylaxis?
Methotrexate/cyclosporine
Features of GvHD?
Rx
Skin: rash
Gut: N+V, abdo pain, diarrhoea, bloody stool
Liver: jaundice
Corticosteroids
What are the common post-transplantation infections?
What is another consideration post-transplantation in the immunosuppressed?
Generally increased risk for conventional infections.
Opportunistic infections can give sevre infections because of immune compromise: CMV, BK virus, PCP
Malignancy:
Viral associated x100: HHV8, EBV
Skin cancer x20
Risk of other cancers also increased
Transplant reactions: What are the features of hyperacute?
Time
Mechanism
Pathology
Treatment
Mins-Hrs
Preformed Ab which activates complement
Thrombosis and necrosis
Prevention: crossmatch
Transplant reactions: What are the features of acute- cellular
Time
Mechanism
Pathology
Treatment
Weeks-Months
CD4 activating a type IV reaction
Cellular infiltrate
T-cell immunosuppression
Transplant reactions: What are the features of acute- Ab-mediated
Time
Mechanism
Pathology
Treatment
Weeks to months
B-cell activation- Ab attacks vessels
Vasculitis, C4d
Ab-removal and B cell immunosuppression
Transplant reactions: What are the features of chronic
Time
Mechanism
Pathology
Treatment
Mths-Yrs
Immune and non-immune
Fibrosis
Minimise organ damage
Transplant reactions: What are the features of GvHD
Time
Mechanism
Pathology
Treatment
Days- weeks
Donor cells attacking host
Skin, Gut, Liver
Prevention/immunosuppression c corticosteroids
Apart from malignancy and infection, what is another post-transplantation complication?
Why?
Athersclerosis/hyperlipidaemia
x20 increased risk in death from MI compared to age-matched general population
Endothelial activation
Clinical features of immunodeficiency
Infections: 2 major or 1 recurrent minor infection
Unusual: organism or sites
Unresponsiveness to oral Abx
Chronic infections
Early structural damage
Suggestive of priamry:
Failure to thrive
Skin rash
Chronic diarrhoea
Mouth ulceration
FHx
How can immunodeficiencies be classified
Primary: congenital
Secondary
Physiological
What are the secondary causes of immunodeficiency?
Infection: HIV, measles, MTB
Biochemical: malnutrition, DM, renal insufficiency, specific mineral deficiency (Zn, Fe)
Malignancy: myeloma, leukaemia, lyymphoma
Drugs: corticosteroids, anti-proliferative immunosuppressants, cytotoxics
Deficienices of barriers to infection:
Epithelial
Burns victims, high risk of infeciton.
>70% of deaths within 5d of burns relate to infection
Deficienices of barriers to infection:
Mucosal barriers and IgA deficiency
Complete deficiency of IgA affects 1:600 caucasians
Associated with recurrent respiratory and GIT infections in 30%
Deficienices of barriers to infection:
Commensal bacteria
Eradication of normal flora with broad spectrum abx resuts in opportunistic infection:
Candida albicans
C. diff
Phagocyte deficiency:
Recurrent infections in skin and mouh:
Recurrent deep bacterial infections: s. aureus, enteric bacteria, MTB and atypical mycobacteria
Recurrent fungal infections: candida, aspergillus fumigates and flavus
How can phagyocyte deficiencies be characterised?
Recruitment: mobilisation from bone marrow, migration to site of infection
Fight and catch microorganisms
Killing of microogransims
Recruitment of other cells
What is a disorder of phagyocyte mobilisation from bone marrow to within tissues?
Reticular dysgenesis: failure of SC to differentiate along myeloid or lymphoid lineage
Feautres of Reticular dysgenesis
Autosomal recessive severe SCID.
Mutation in AK2 (mitochondrial energy metabolism enzyme)
What is a disorder of failure of neutrophil maturation
Cyclic neutropenia
Kostmann syndrome
What is cyclic neutropenia?
AD episodeic neturopenia every 4-6w due to mutation in neutrophil elastase ELA2
What is Kostmann syndrome?
AR severe congenital neutropenia, classical form due to mutation in HCLS1-associated protein X-1?
What is classically due to mutation in HCLS1-associated protein X-1?
Kostmann syndrome: AR severe congenital neutropenia
What is a disorder of failure of phagocyte migration to site of infection?
Leukocyte adhesion deficiency (CD18 deficiency)
What is CD18
B2 integrin subunit
Features of leukocyte adhesion deficiency?
CD11a/CD18 and CD11b/CD18 are expressed on neutrophils, bind to ligands on endothelial cells and regulat neutrophil adhesion/transmigration.
In leukocyte adhesion deficiency, the lack of these molecules means the neutrophils fail to leave the blood stream.
Characterised by very high neutrophil counts in blood and the absence of pus formation
Characterised by very high neutrophil counts in blood and the absence of pus formation
Leukocyte adhesion deficiency
What is a disorder of a failure to find and catch microothanisms?
Failure of endocytosis and formation of phagolysosome
Complement deficiency and antibody production will result in failure of opsonisation
What is a disorder characterised by failure in oxidative/non oxidative killing?
Chornic ganulomatous disease
Features of chronic granulomatous disease?
Absent respiratory burst: deficiency in one of hte components of NADPHO: inability to generate O free radicals leading to impaired killing of intracellular microorganisms
Excessive inflammation: persistent neutrophil/macrophage accumulation with a failure to degrae antigens leading to granuloma formation.
Lymphadenopathy and hepatosplenomegaly
Ix in chronic granulomatous disease?
Basis is whether neturophils can kill through the production of oxygen radicals- activated neutrophils will stimulate respiratory burst and produce H2O2
NBT
Dihydrorhodamnie flow cytometry
What is NBT?
Nitroblue tetrazolium test- dye will change from yellow to blue when interacted with H2O2:
Chronic granulomatous disease-> no H2O2
What is dihydrorhodamine flow cytometry?
DHR is oxidisaed to rhodamnie which is strongly fluorescent when it interacts with H2O2
No H2O2-> chronic granulomatous disease
What is a disroder of phagocyte failure to recruite other cells?
IL-12/IL-12R
IFNg/IFNgR
Deficiency
Features of IL-12 or IFNg deficiency
Infection with MTB stimulates IL-12 IFNg network
Infected macrophages produce IL-12 which induced T-cells to secrete IFN gamma which feedsback to macrophages and neutrophils to produce TNF, activating NADPHO and stimulating oxidative pathways.
Defect in this pathway leads to susceptibility to mycobacterial infections
What is the approach to treating phagocyte deficiencies?
Aggressive management of infection: infection prohpylaxis: septrin (abx), itraconazole (anti-fungal). Oral/IV Abx as needed. Drainage of abscesses.
Definitive therapy: BM transplantation to replace defective population. Specific treatment fo chronic granulomatous disease= IFNg therapy
What are the clinical features of T cell deficiency
Increased susceptibility to:
Viral infections (CMV)
Fungal (penumocystis, cryptosporidium)
Some bcaterial esp. MTB, salmonella
Early malignancy
What are the clinical features of Ab deficiency or CD4 T cell deficiency?
Bacterial infections (Staph, strep)
Toxins (tetanus, diptheria)
Viral infections: enterovrius
What is reticular dysgenesis?
Most severe form of SCID, mutation of AK2
Failure to produce: neutrophils, lymphocytes, monocytes, macrophages and platelets.
Fatal in early life unless corrected with a BM transplant
How can deficiences of the adaptive immune system be classified?
Defects of haemopoetic stem cells
Defects of lymphoid precuross
Defects in T cell maturation/selection in the thymus
Defects in T cell effector function
What is the defect of haemopoetic stem cells leading to deficiency in the adaptive immune system?
Reticular dysgenesis- SCID
What is the cause of defects in lymphoid precurors leading to deficiency in the adaptive immune system?
Other forms of SCID
Features of SCID
Unwell by 3 months
Infections of all types
FTT, persistent diarrhoea
Unusual skin disease: colonisation of the empty bone marrow by maternal lymphocytes- graft vs host disease.
Fhx of early infant death.
Neonate protected from SCID by maternal IgG in first 3/12
What are the causes of SCID?
20 pathways identified: deficiencies of cytokine Rs, singalling molecules or metabolic defects.
Specific mutation will have a different effect on the lymphocyte subset.
Features of X-linked SCID
45% of all SCID
Mutations of gamma chain of IL-2 receptor on chromosome Xq13.1
Shared by receptros for IL-2, 4, 7, 9, 15 and 21.
Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells.
Phenotype: very low or absent T cell numbers
Normal or increased B cell numbers
Poorly developed lymphoid tissue and thymus
Mutations of gamma chain of IL-2 receptor on chromosome Xq13.1
X-linked SCID
What are the causes of T-cell deficiency due to defective maturation/selection in the thymus?
Di George syndrome
Bare lymphocyye syndrome
What are the features of DiGeorge syndrome
Developmental defect of the 3rd and 4th pharyngeal pouch resulting in congenital thymic apalsia.
AD
75% sporadic deletion at 22q11
Phenotype: normal B cell numbers, reduced T cell numbers. Homeostatic proliferation with age and improved function with age
High forhead, low set abnormally folded up ears. Cleft palate. Small mouth and jaw, hypocalcaemia, oesophageal atresia, T cell lymphopenia and complex congenital heart disease
High forhead, low set abnormally folded up ears. Cleft palate. Small mouth and jaw, hypocalcaemia, oesophageal atresia, T cell lymphopenia and complex congenital heart disease
DiGeorge
Deletion at 22q11
DiGeorge
DiGeorge
Features of bare lymphyocyte syndrome Type 2
Defect in one of the regulatory proteins involved in HLA-II expression (regulatory factor X class II transactviator)
No expression of MHCII
Profound deficiency of CD4, usually have normal CD8, normal B cells with a failure to make IgG or IgA Ab.
Type1: failure to express HLAI
Clinical phenoytpe: unwell by 3/12, infections of all types, FTT, can be associated with sclerosing cholangitis.
Fhx of early infant death
What are the defects in T cell effector function leading to immunodeficiency?
Defects in cytokine production, receptor, cytotoxicity or T-B cell communication
e.g. IL-12 IFNg vs MTB
Cytokine R/ secretion deficiency,
Ix in T cell deficiency
Total WCC and differential (NB WCC much higher in children than adults)
Examine lymphocyte subsets: quantify CD8, CD4, DB cells and NK cells
Serum IgG and protein electrophoreisis (IgG prod is a surrogate marker for CD4 celll function)
Functional test of T cel activation and proliferation
HIV test
Mx of T cell deficiencies
Infection prophylaxis
Aggressive treatment of infection
Ig replacement
BM transplant: to replace abnormal population in SCID, to replace abnormal cells
Gene therapy
Thymic transplantation: DiGeorge
Features of Brutonj’s X-linked hypogammaglobulinaemia
Affects B cell maturation
Defective B cell RtK gene
Pre-B cells cannot develop to mature B cells, therefore there is an absence of mature B cells.
No circulating Ig after 3/12
Recurrent infections during childhood, bacterial and enterovirus
Features of selsective IgA deficeincy
2/3rd asymptomatic
1/3rd have recurrent RTI
There is a genetic component, as of yet unidentified
Features of Hyper IgM syndrome
X linked, no IgG, E or A. IgM B cells and plasma cells are present
Clinical phenotype: boy will present in the first few years of life with recurrent infection, bacterial. FTT. Can have PCP, autoimmune disease and malignancy
Normal numbers of circulating B cells and normal T cell numbers with normal T cell in vitro responses.
Elevated IgM with undetectable IgG, IgE and IgA
No germinal centre development within LNs and spleen.
Failure of isotpye swithching
Pathology of Hyper IgM
T cell defect
Mut in CD40 ligand gene. (Member of TNFR, involve in T-B cell communication- expressed by activated T cells)
Failure to express CD40L on activated T cells means T cells are unable to help B cells resulting in no cross talk and failure of Ab switching.
Causes a secondary defect in B celll maturation.
Intrinsic T cell defect
Features of Common Variable Immune Deficiency
Heterogeneous group of disorders with unkown mechanism
Clinical features:
Low IgG, IgA and E
Recurrent bacterial infections, often with severe end organ damge: bronchiectasis, persistent sinusitis, recurrent GI infection
Autoimmune disease
Granulomatous disease
Ix in B cell deficiency
Total WCC and differenital.
Lymphocye subsets
Serum Ig and electrophoreisis.
Functional tests of B cell function:
Specific Ab responses to known pathogens
Measure IgG against teatanus, H influenza b and pneumococcus. If specific Abs are low, immnise and repeat measurement 6-8w later
Mx of B cell deficiency
Aggressive mx of infection
Immunological replacement: derived from pooled plasma of donors, contains IgG Abs to a wide variety of common organisms. Lifelong IgG every 3-4w
BM transplant
Immunisation for selective IgA deficiencies
Features of complement deficiency
Infection: particularly with encapsulated bacteria if the alternative and terminal pathways are involved:
N. meningitides- meningococcus
Step pneumonia
GBS
H. infl
Fhx of infections
SLE if early componenets of the classical pathway are involved
Draw the complment pathway
Features of early calssical pathway deficiencies
C1, C2, C4
Immune complexes fail to activate complement pathways, leads to increased susceptiblity to infection.
Early complement is involved in clearance of apoptotic and necrotic cells-> deficienes result in increased load of self Ags, particularly nuclear components-> SLE
Complement activation normally promotes solubilisation of immune complexes. Deficiencies tresult in deposition of immune complexes which stimulate local inflammation in skin joints.
Types include C1q, C1r, C1s, C2 and C4
What is the most common early complement deficiency
C2
Phenotype of complement deficiency
Almost all patients with C2 have SLE
Usually severe skin disease, also increased incidence of infections
Features of MBL pathway deficiency
30% of individuals are heterozygous for mutant protein
6-10% have no ciruclating MBL
Associated with increased infection in patients who have another cause for immune impairment
Features of alternative pathway deficiencies
Inability to mobilise complement rapidly in response to bacterial infections
Clinical: infections with encapsulated bacteria
Very rare
Features of C3 deficiency
Severe susceptiblity to bacterial infections
Increased risk of developing connective tissue disease
Features of deficiency in terminal pathway of complement
Inability to make MAC
Inability to use complement to lyse encapsulated bacteria
N meningitis
S pneumonia
H infl
Features of secondary complement deficiencies
Active lupus causes persistent production of immune complexes and consequent consumption of complement leading to functional complement deficiency
Nephritic factors are autoAbs direceted against components of the complement pathway
C4NeF: nephritic factor of the classical pathway
C3NeF: nephritic factor of the alternative pathway
Nephritic factors stabilise C3 convertase resulting C3 activation and consumption
Often associated with GN, classically memranoproliferative
Ix of complement deficiency
Quantification of complement pathway: C3 and 4 routinely measured. C1 inhibitor decreased in angioedema
Functional complement tests
CH50 complement test
Classical pathwayq
AP50 complement test
Alternative pathway
Mx of complement deficiency
Vaccination
Prophylactic Abs
Treat infections aggressively
Screen family members
What are the functions of the spleen
Clearance of debris: filtering and phagocytosis of particulate matter. Selective removal of dead and dying cells. Removal of red cell inclusions, bacteria and immune complexes
Immune response to infection: reservoir of lymphocytes, site activation and maturation of B and T cells
What conditions are associated with functional hyposplenism?
Congenital asplenia
Haematological disorders: SCD, thalassaemia major, lhymphoproliferative (HL, NHL, CLL), post BM transplant
Gastro disorders: Coeliac, IBD
Connective tissue disease: SLE and RA
What are the implications of hyposplenism
Increased incidence of infection: risk of severe infection x40, risk of fatal sepsis x17
Strep penumonia
H. infl
Meningococcus
Malaria
Other: capnocytophaga canimorsus (dog bites), babesiousus (protozoal infection, tic bites), E Coli, S aureus, GBS, pseudomonas
Mx hyposplenism?
Immunisation: s penuonia, H influenza, Meningococcus, IFV. Most infections occur during 2 years after splenectomy, risk is lifelong
Antibiotics: low dose prophlyactic penicillin V or erithromycin. Keep broad spectrum antibiotics at home and can be started when symptoms of infection
Medic alert bracelet: no functioning spleen
Take prophylaxis when travelling
Seek attention after animal or tick bites
Antibiotic prophylaxis in hyposplenism
penicillin V or erithromyic for at least 2y after splenectomy
Draw T cell deficiencies
Draw B cell deficiencies
Draw neutrophil deficiency
Where is IgA found?
Mucosal areas, saliva, tears, breast milk
IgE function
Allergy, histamine release from mast cells
IgG significance
Can pass transplacentally
Immature B cells express which Ig?
IgM
Bacterial infections in CGD?
PLACESS
Particular susceptibility to catalase positive organisms:
Pseudomonas
Listeria
Aspergillus
Candida
E coli
Staph aureus
Serratia
Prophylactic treatment of CGD?
Trimethoprim
Itraconazole
IFN
Treatment of cyclic neutropenia
G-CSF
What are the two types of latex allergy
Type 1 hypersensitivity: classical spectrum
Type IV hypersensitvity: contact dermatitis
Features of type 1 hypersensitivity to latex
Acute onset of classcial symptoms, spectrum of severity
Mucosal route associated with more severe reactions.
Occupational exposure
What specific patient groups are at more risk of Type 1 hypersensitvity reaction to latex?
spina bifida, CP, patients undergoing multiple urological procedures, preterm infants, pts with indwelling latex devices
What substances have cross-reactivity to latex?
Avocado
Apricot
Banana
Chestnut
Kiwi
Passion fruit
Papaya
Pear
Pineapple
Dx of Type 1 latex hypersensitivity?
Test specific IgE to latex
Features of Type IV hypersensitivity to atex
Contact dermatitis
Usually affects hands or feet due to glove or rubber footwear and it is mainly due to rubber additvies e.g. thiuram rather than latex itself
24-48h post exposure and characterised by pruritis
Rash is well demarcated and often flaky.
No response to anti-histamines
Dx of type IV hypersensitivity to latex
Patch test: moisten blotting paper with susepcted allergen and tape to healthy area of skin for 24-48h
Eczma will be seen where substance is in contact with skin
Bx will confirm infiltrating T cells and granuloma formation
SPUR
Immune deficiency
Serious
Persistent
Unsual
Recurrent infections
Immunological causes of recurrent meningococcal meningitis
Neurological
Complement deficiency
Ab deficiency
BBB disruption e.g. occult skull #, hydrocephalus
What is CH50
Functional test of the classical complement cascade. All components must be in place to give a positive (normal) result
What is AP50
Functional test of the integrity of the alternative pathweay (bacterial cell wall, properdin, factor B, H I) all components must be in place to give normal result
ANA +ve Result, action
anti-dsDNA
Test complement levels: consumption of complement (i.e. low levels of C3 and C4 suggest active lupus)
Kidney funciton:
Urinalysis
Urine microscopy
Renal biopsy
Features of serum sickness
Caused by exposures to antibodies dervide from animals or some drugs e.g. penicllin based medicines.
Penicllin can bind to cell surface proteins hich can act as a neo-antigen and stimulate a very strong IgG response leading to penicllin.
After sensitisation, subsequent exposures will form immune complexes with the circulating penicllin resulting in increased IgG production. Results in immune complex deposition, complement activation and macrohpage infiltrationa nd neutrophils.
Small vessel vasculitis occurs.
IgG deposition in glomeruli, skin and joints causes renal dysfunction, purpuric rash and arthralgia
Clinical features of serum sickness as a result of penicllin
Fever
Arthralgia
Vasculitic skin rash
Renal function deterioriation
Increasing disorientation
Ix in serum sickness
ESR
CRP
LFTs
all increase
Urine microscopy will show blood and protein
Low complenet (classical pathway)
Specific IgG to penicllin
Biopsy: skin or kidney, macrophages and neutrophil infiltrations
Serum sickness, cause of:
Disorientation
Small vessel vasculitis affecting cerebral vessels may compromise oxygen supply to the brain
Serum sickness, cause of:
Purpura
Leakage from inflamed vessels
Local haemorrhage
Clots
Compromised O2 delivery
Mx of serum sickness
Discontinue penicillin
Corticosteroids to decrease inflammation
Fluid management
Prednisolone
Widely used immunosuppressant
Pegylated IFNa
Effective in some inflammatory disease e.g. Behcets
Azathiorpine
Widely used anti-proliferative immunosuppressnat
Check TPMT status before use
What is the importance of TPMT status?
TPMT is measured in patients who are about to start treatment with thiopurine drugs such as azathioprine. TPMT activity varies in the population and this means that different people require different doses of thiopurine drugs to get the desired therapeutic effects. Guidance in the UK recommends that patients commencing thiopurine drugs have their TPMT status checked before treatment begins. The test identifies individuals at risk of developing severe side effects such as lowering ofblood cell counts and a lowered immune response.
Hydroxycholoroquine
Alters pH and affects Ag presentation/processing
Inhibits production of some cytokines
Upregulates apoptosis/clearance
Allopurinol
Xanthine oxidase inhibitor used in gout
Rituximab
Antibody to CD20 that depletes B cells
IVIG
Effective immunosuppressive agent
Precise mechanisms unclear
Used in SLE, Dmy, Pemphigus
Myclophenolate mofetil
Anti-proliferative immunosuppressant wthi preferntail effect on lymphocytes
Adalimumab
Anti-TNFa Ab
May precipitate cutaenous lupus
Cyclophosphamide
Cytotoxic immunosuppressant
Colchicine
Inhibits neutrophils
Used in gout, Behcets
What is the cause of increased susceptibility to infection in MM?
Suppression of production of normal IgG by the malignant clone results in a functional Ab deficiency= immune paresis
Why does the post-partum presentation of RA occur?
Due to changes in Th cell profiles.
Th2 dominates in pregnancy
Th1 postpartum
How to ensure a good response to vaccination?
Good antigen with a variety of epitopes
Sufficeint dosage
Administration via appropriate route?
What are the best routes for vaccine administration?
SC good uptake and processing
IM ok
IV Ag: taken to spleen
Oral is good locally
Intranasal is good but may lead to an allergic response
Vaccination schedule
2months
5 in 1: diptheria, tetnaus, pertussis, polio, H. influenza
Pneumocccal vaccine
Rotavirus
Men B (new vaccine introduced Sept 2015)
What is the 5 in 1 vaccine?
Diptheria, tetnaus, pertussis, polio, haemophilus
Vaccination schedule
3 months
5 in 1 vaccine, second dose
Men C
Rotavirus, second dose
Vaccination schedule
4 months
5 in 1, third dose
Pneumococcal, second dose
Men B, second dose
Vaccination schedule
1y
Hib/Men C booster
MMR
PCV, third dose
Men B, third dose
Vaccination schedule
2-6y
Children’s flu vaccine
Vaccination schedule
3 years and 4 months
MMR, second dose
4 in 1 pre school booster: diptheria, tetanus, pertussis, polio
Vaccination schedule
12-13y/o
Girls only
HPV-, two injections given between 6m and 2y apart
Vaccination schedule
14y/o
3 in 1 teenage booster: diptheria, tetanus, polio
Men ACWY
Vaccination schedule
>65y/o
Flu annually
Pneumococcal pneumonia vaccine
Vaccination schedule
70y/o
Shingles vaccine
What is the difference between a Th1 and Th2 response?
Th1 is cell mediated: Il-2, IFNg, TNF
Th2 is humoral: IL4, 5 6
Features of IFV vaccine
Protection conferred by antibody to HA rather than the cytotoxic CD8+ cells, which control the viral load
HA: receptor biding and membrane fusion glycoprotein
Response maintenance: begins within 1/52 and can last 6/12 or longer
Features of TB vaccination
Protection conferred by T cell response
Maintenance of response lasts 10-15y
Mantoux Test
Injection of 0.1ml of 5 tuberculin units purified protein derivative. Examine arm after 48-72h
Reaction is an area of unduration around the site.
>10mm= +ve result, implies previous TB exposure or BCG
How can immunological memory be measured?
Presence/amount of IgG
Presence of memory T cells (CD45RA and CD45RO)
either numerical or functional tests
What are the characteristics of immunological memory?
Subsequent exposures are more rapid and aggressive
There are different patterns of the expression of cell surface proteins which allows lymphoid cells access to non-lymphoid tissue
Longevity: memory T cells are maintained without continual antigen by low level prolifeation in response to cytokines like IL2, 7 and 15
What are the CD types for memory T cells?
CCR7+/ CD62L high
Migrate efficiently to peripheral LNs and produce IL-2 (no IFN gamma or perforin)
CCR7 is involved in extravastion
CD62L interacts with molecule on HEV wihich mediates attachment and rolling
What are the CD types ofr effector memory cells?
CCR7- CCR62- Low
Not found in LNs but are in other sites
Produce little IL2 but lots of IFNg and perforin
What are the advantages of live vaccines?
Establishes infection with weak/absent symptoms
Lifelong immunity
Activates all arms of the IR: humoral and local
Immunity to multiple antigens which is more durable due to cross reactivity
What are the disadvantages of live vaccines?
Possible reversion to virulance e.g. vaccine associated paralytic poliomyelitis
Storage problems
Safety issues
Problems in people with immunodeficiency
e.g. of live vaccines?
Yellow fever
MMR
Typhoid
TB
Polio
Vaccinia
E.g. of inactivated vaccines?
IFV
Cholera
Bubonic plaque
Polio (Salk)
Hep A
Pertussis
Rabies
Toxoid vaccines
Diptheria
Tetanus
Components/ subunit vaccines?
Hep B antigen (HbS antigen)
HPV (Caspid)
IFV (HA or NA)
E.g. conjugate vaccine
Hib
Meningococcus
Penumoccocus
Advantages of inactivated/component vaccines
No mutation or reversion
Can be used with immunodeficient
Can lead to elimination of WT virus from community
Easier storage
Low cost
Disadvantages of inactivated/component vaccines?
May have poor immunogenicity
Multiple injections
Adjuvants
Often does not follow normal route of injection
Mechanism of DNA vaccines?
Plasmid containing antigen gene is inserted into a mucsle cell where the Ag is replicated. The gene expressed at the cell surface induces an immune response
Advantages of DNA vaccines
Easy production
Stable
Will ressemble a virally infected cell
Immunogenic
MHCI driven
Disadvantages of DNA vaccines
Plasmid could integrate into host DNA
Autoimmune
What is a depot adjuvant?
Adjuvant which increases the IR without altering its specifcity
Release of the antigen is slowed providing a steady stream of antigen exposure
Freund’s adjuvant
What is Freund’s adjuvant?
Oil based depot adjuvant
Alum as an adjuvant
Ag absorbed into Alum and is slowly released.
Alum also immunogenic in itself as it activates Gr1+ cells which produce IL4 and prime naive B cells.
Alum is the primary adjuvant utilised in humans
What is complete Freund’s adjuvant?
Water in oil emulsion containing MTB cell wall componenets
No longer used clinically
Why are the elderly more likely to die of a vaccine-preventable disease?
Immune senescence: increased frequency of terminally differentiated effector memory T cells in the elderly.
Nutrition: failure to mount an adequate response to some vaccines due to a lack of energy due to poor nutrition
CD45RO T cells=
Memory
CD45 RA T cells=
Effector cells
CPG adjuvant
Unmethylated motife used as an immunostimulatory adjuvant
ISCOMs
Immune stimulating complex used as vaccine adjuvant
Experimental multimeric antigen with built in adjuvant
Human Normal IG
Hep A and Measles
HBIG
Hep B Ig
HRIG
Human rabies Ig
VZIG
Varicella zoster Ig
Paviluzimab
Monoclonal Ab for RSV
Ix in fatigue
FBC
U&E
Creatinine
Calcium
LFTs,
Glucose
Thyroid function testss
Causes of microcytic anaemia
Fe deficiency
Thalassaemia
Anaemia of chronic disease
Fe deficiency
Hb
Serum Fe
TIBC or transferrin
Transferrin saturation
Ferritin
Low
Low
Raised
Low
Low
Ferritin
Ferritin is an ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including algae, bacteria, higher plants, and animals. In humans, it acts as a buffer against iron deficiency and iron overload.[3] Ferritin is found in most tissues as a cytosolic protein, but small amounts are secreted into the serum where it functions as an iron carrier. Plasma ferritin is also an indirect marker of the total amount of iron stored in the body, hence serum ferritin is used as a diagnostic test for iron deficiency anemia.
TIBC
Total iron-binding capacity (TIBC) or sometimes transferrin iron-binding capacity is a medical laboratory test that measures the blood’s capacity to bind ironwith transferrin.[1] It is performed by drawing blood and measuring the maximum amount of iron that it can carry, which indirectly measures transferrin[2] since transferrin is the most dynamic carrier. TIBC is less expensive than a direct measurement of transferrin.[3][4]
TIBC
Transferrin saturation, abbreviated as TSAT and measured as a percentage, is amedical laboratory value. It is the ratio of serum iron and total iron-binding capacity. Of thetransferrin that is available to bind iron, this value tells a clinician how much serum iron are actually bound. For instance, a value of 15% means that 15% of iron-binding sites of transferrin are being occupied by iron. For an explanation of some clinical situations in which this ratio is important, see Total iron-binding capacity. The three results are usually reported together.
Blood film in coeliac
Hypochromic microcytic cells
Poikilocytes (abnormal shapes)
Anisocytosis (size)
Basophilic stippling (aggregated ribosomal material- also seen in ETOHism, lead poisoning, sideroblastic anaemia and beta thalassaemia)
Target cells: high SA:volume ratio
Blood film in Fe deficiency
Hypochromic and microcytic with anisopokilocytosis
Anaemia of chronic disease
Hb
Serum Fe
TIBC
Transferrin saturation
Ferritin
Low
Low
Normal or low
Normal
Normal or high (acute phase marker)
Thalassaemia
Hb
Serum Fe
TIBC
Transferrin saturation
Ferritin
Normal or low
Normal
Normal
Normal
Normal
Blood film in hyposplenism
Howell-Jolly bodies (nuclear remnants)
Target scells
Causes of Fe deficiency
Poor diet
Blood loss
Malabsorption
Combination of above
Causes of hyposplenism
Absent spleen
Poorly functioning spleen: IBD, coeliacs, sickle cell, SLE
Blood film in megaloblastic anaemia
Hypersegmented neutrophils (problem with DNA synthesis)
Macrocytic
Causes of megaloblastic anaemia
B12 or folate deficiency
(poor diet, malabsorption, pernicious anaemia)
DDx of bowel disease with malabsorption
Coealiac
Crohns
Another dx e.g. menorrhagia, pancreatic disease, bacterial overgrowth, tropical sprue, thyrotoxicosis, post-sx, lymphoma, zollinger-ellison
Ix of coeliac
CRP and ESR
Serological tests: anti-endomysial, anti-ttg
Upper GI endoscopy and distal duodenal biopsy
First line antibody in coeliacs?
Anti-TTG
IgA anti-endomysial
Sensitivity 85-94%
95% specific
Will disappear after several months with adoption of a gluten free diet
Anti-TTG
Coeliacs
90-94% sensitivty
95% specific
Correlates with anti-endomysial
What is an issue with anti-endomysial and anti-TTG
Both IgA
Therefore not useful in IgA deficient patients
Anti-gliadn IgA
57-80% sensitivty, 30-50% specficity
Will persist after adoption of gluten free diet
What is the gold standard for dx of coeliac
Duodenal histology
HLA associations in coeliac?
HLA-DQ2 (90%)
others carry DQ8
Pathophysiology of Coeliac
Peptides from gliadin deamidated by TTG and presented by APC
CD4 cells recognise these peptides which are presented by HLA DQ2 or 8 forming immune complex
CD4 activation leads to secretion of IFNg and IL-15
IL-15 promotes activation of intra-epithelial lymphocytes
IELs kill epithelial cells in a NKG2D dependent manner.
Primed gliadin specific T cells provide help for B cells whose surface receptors.
These produce Abs to gliadin. Other B cells primed for TTG and produce IgAs for tese
Villous atrophy, crypt hyperplasia
Villous height: crypt 3:5
|ncreased IEL
Coeliacs
Histopathology in Coeliacs
Villous atrophy, crypt hyperplasia
Villous height: crypt 3:5
|ncreased IEL
Coeliac
Mx of Coeliacs
Dietary management
Advice re LT compiications
Sources for patient information
What foodstuffs contain gluten
Wheat
Barley ryes
Oats
Gluten free food?
Rice, corned beef, eggs, chips, wine
Cxs of coelacs
Malabsorption
Osteomalacia and osteoporosis
Neurological disease (epilepsy, cerebral calcification)
Lymphom
Hyposplenism
Mortality x2-3 normal population but normalises after 3-5y gluten free
What autoimmune diseases are associated with coeliacs?
Dermatitis herpetiformis (100%)
T1DM (7%)
Autoimmune thyroid disease
DS
SLE, AI hepatitis, AI Addison’s, recurrent apthyous ulceration, Sjogren, sarcoid, vitiligo, alopecia, IgA deficiency
FU Ix in coeliac
Haematology: FBC, Iron studies, Vit B12 and folate, PT time
Biochemistry: U&E, creatinine, Ca and P, LFTs, albumin, total serum protein levels
Serological: quanititaive igA anti-TTG or anti-endomysial
Imaging: DEXA of spine and hip every 3-5y
Indications for testing for coeliacs
Fe def anaemia
Crhonic diarrhoea
Recurrent mouth ulcers
IBS
Chronic fatigue
Unexplained weight loss
FTT
Epilepsy
Peripheral neuropathy
Infertility
FHx of coeliacs
T1DM
DS
AI thyroid disease or vitiligo
Dermatitis herpetiformis
Autoimmune vs autoinflammatory
Autoimmune is an adaptive immune response, can be monogenic or polygenic. Aberran B and T cell responses in primary and secondary lymphoid organs lead to breaking of tolerance and development of immune reactivity towards self-antigens
Autoinflammatory: innate immune responses can be monogenic or polygenic. Local factors at sites predisposed to disease lead to activation of innate immune cells e.g. neutrophils and macrophages resulting in tissue damage
Give 2 examples of monogenic autoinflammatory diseases
Familial Mediterranean fever
TRAPS
What is TRAPS?
TNF receptor associated periodic syndrome
TNRSF1 mutation of TNF receptor.
Periodic fever, rash abdo pain
TNRSF1 mutation of TNF receptor.
Periodic fever, rash abdo pain
TRAPS
What is Familial Mediterranean Fever
MEFV mutation leading to defective pyrin-marenostrin.
AR from people around the mediterranian sea
Sephardic> Ashkenazy Jews, Armenian, Turkish and Turkish
Pyrin marenostrin expressed in neutrophils. There is a failure to regulate cryopyrin driven activation of neutrophils
Periodic fever lasting 48-96 hours
Associated with abdominal pain, arthritis, chest pain, myalgia
LT risk of amyloidosis: nephrotic syndrome and renal failure
Familial mediterranean fever
Rx of Familial Mediterranean Fever
Colchicine 500ug BD
Anakinra: IL-1R antagonist
Etanercept: TNF alpha inhibitor
What are three examples of monogenic autoimmune disease?
APS-1
ALPS
IPEX
What is APS1?
Autoimmune polyendocrine syndrome (Candidiasis-Hypothyroidisim-ADdison’s disease)
AR defect in AIRE (TFactor) involved in T cell immunotolerance in the thymus
Abs vs endocrine tissues
Mild immunodeficiency leads to candida infections
AR defect in AIRE (TFactor) involved in T cell immunotolerance in the thymus
ALPS1
What is IPEX
Immune dysregulation, polyendocrinopathy, enteropathy, X linked syndrome
Mutation in Foxp3 which is required for Treg development.
Overwhelming disease leads to early death without treatment
Usually insulin dependant DM with autoantibodies, thyroid disease, Diarrhoea, eczematous dermatitits
Mutation in Foxp3 which is required for Treg development.
IPEX
What is ALS
Autoimmune lymphoproliferative syndrome
FAS pathway mutations e.g. TNRSF5 which encodes FAS. Leads to defect in Fas-mediated apoptosis. Leading to a chronic non-malignant lymphoproliferation, autoimmune disease and secondary cancers.
Commonly autoimmune cytopenias e.g. AIHA, neutropenia or thrombocytopenia.
High lymphocyte numbers with large spleen and LNs, may be associated with lymphomas
FAS pathway mutations e.g. TNRSF5 which encodes FAS. Leads to defect in Fas-mediated apoptosis. Leading to a chronic non-malignant lymphoproliferation, autoimmune disease and secondary cancers.
Commonly autoimmune cytopenias e.g. AIHA, neutropenia or thrombocytopenia.
High lymphocyte numbers with large spleen and LNs, may be associated with lymphomas
Autoimmune lymphoproliferative syndrome
Give some examples of polygenic autoinflammatory diseases
Crohn’s
UC
Osteoarthritias
GCA
Takayasu’s arthritis.
Features of Crohn’s
IBD1-8 is NOD2 which enodes for CARD-15. mutations in these genes associated with Crohn’s
30% have mutation.
Abdo pain, tenderness, diarrhoea (blood, pus, mucus), fever, malaise oral ulcers, pyoderma gangrenosum, arthritis, raised inflammatory markers
What proportion of Crohn’s patient have NOD2 mutations?
30%
NOD2 CARD-15=
Crohn’s
Features of GCA
Most common systemic vasculitis in the elderly. Affects aorta and cranial branches- temporal artery arising from the external carotid and the opthalmic artery arising from the internal.
Associated with a number of genetic polymorphisms
Temporal headache, claudication pain on chewing, visual loss
Temporal headache, claudication pain on chewing, visual loss
GCA
Ix of GCA
High CRP and ESR
Abnromal temporal biopsy with intimal proliferaiton, disrupted internal elastic lamina and mononuclear cells throughout the vessel wall
Abnromal temporal biopsy with intimal proliferaiton, disrupted internal elastic lamina and mononuclear cells throughout the vessel wall
GCA
What are some examples of mixed pattern auto diseases?
Ank spond
Psoriatic arthritis
Behcet’s
Rx in GCA
High dose corticosteroids.
Immunosuppression LT
Features of ank spond
Inflammatory disease primarily of the axial skeleton
>90% heritability of disease factors.
HLA-B27 there is an environmental trigger: enteric bacteria
Enhanced inflammation at sites of high tensile forces- enthuses: site of instertions of ligaments or tendons.
HLA-B27 associated with?
Ank spond
Lower back pain and stiffness, worse after rest, pain and swelling affecting hips and kness.
Enthesitis
Dactylitis
Uveitis
Ank spond
Rx of ank spond
NSAIDs
Biologic: TNF alpha antagonists
Gives some examples of polygenic autoimmune disease
RA
MG
Pernicious anemia
Addison’s
SLE
PBC
HLA-DR15 associated with
Goodpasture’s
HLA-DR3 associated with?
Grave’s, SKE, T1DM
HLA-DR4 associated with
T1DM, RA
What are the features of central tolerance in T cells
pre-T cells from the BM undergo negative selection for high affinity HLA or neglect for low affinity HLA
What are the features of central tolerance in B cells?
Tolerance occurs in the BM. Self-reactive B cells are deleted. Immature B cells are deleted by polyvalent antigens.
Only the immature B cells that have no cross-linking survive
What are the mechanisms of peripheral tolerance?
Anergy
Regulatroy Cells
Immune privilege
What is anergy
Lack of co-stiumlating molecules means T cells will not respond to subsequent challenge. CD40/CD40L. CD800/86-28
What is the mechanism for peripheral tolerance through regulatory cells
Decreased number of regulatory cells can lead to AID
T regs: IPEC
Tr1 cells= IL10 secreting
CD8 regulatory cells
How does immune privilege lead to peripheral tolerance
Lymphocytes are denied enry e.g. eye, CNS, testes.
Damage to these sites can cause AID
What is the Gel-Coombs classification
Relates to the effectory mechanism of tissue damage rather than the autoimmune repsonse.
What is Type I hypersensitivity
e.g.
Immediate hypersenstivity which is mediated by IgE
e.g. atopy, anaphylaxis, asthma
What are the features of a Type I hypersensitivity reaction?
Rapid allegic reaciton when the allergen binds to preformed antibodies.
Antgen binding leads to cross linking and mast cell degranulation
This leads to the release of preformed inflammatory mediators e.g. histamine, serotonin, proteases as well as a delayed reaction due to synthesised mediators e.g. leukotrienes, prostaglandins, bradykinin and cytokines.
Leads to incresaed vascular permeability, smooth muscle contraciton and leukocyte chemotaxis
What is Type II hypersensitivity?
Cytotoxic HS. Antibody reacts with cellular antigen.
e.g. pemphigus vulgaris: epidermal cadherin causes skin blisering.
Goodpastures: non collagenous daamage of BM
AIHA: Rh blood group anitgen.
Often causes autoimmunity
What are the featurse of type II hypersensitvity
Auto-ab binds to a cell or amtrix associated antigen on the affected organ cells. Results in antibody dependant cell dest5rcution via complement, NK cells or phagocytes
Complenet: classical pathway
NK: release of cytotoxic granules
Phagocytes: phagotcytosis
What is a Type V HS response
Receptor activation or blockaed.
Instead of binding to cell surface components as in a Type II reaction, Abs recognise and bind to cell surface receptros which either prevent the intended ligand binding to the receptor or mimic the ligand e.g. Grave’s. MG
What is a type III hypersensitivity reaciton?
Immune complex-HA
e.g. cryoglobulinaemia.
SLE
Serum sickness
Features of a type III hypersensitivity raction
Antibody reacts with a soluble antigen to form an immune complex.
Immune complex deposited in BVs which can activate complement and initiate macrophage and neutrophil infiltration.
Overall result is inflamamtion and damage to the vessels.
Symptoms include fever, vasculitis, arthritis, nephrtiis.
Usually immune complexes are cleared but they persist in autoimmune disease
What is a type IV hypersensitivity response?
e.g.
Delayed- T cell mediated
T1Dm
MS
Allergic contact dermatitis
Psoriarsis
Features of Type IV hypersensitivity
MHC1 cells present a self-pepdite which is recongised by CD8 cells, whic perform cytotoxic function leading to cell death.
MHCII present self-antigens to the CD4 cells. Along with a costimulatory signal, this results in IFNg release activating macrophages. This results in tissue damage.
The Th1 CD4 cells need to have been previously primed to react to the self-antigen.
Pathophysiology of Type I Hypersensitivity
Immediate reaciton as a response to re-exposure to an allergen
IgE mediated: mast cells release mediators resulting in vasodilation, increased permeability and smooth muscle spasm
Typica symptoms of a T1H reaction
Angioedema
Urticaria
Rhinoconjunctivitis
Wheeze
D+V
Anaphylaxis
Atopy=
Produciton of a specific IgE response to common environmental allergy
Allregy=
Development of a T1H to an environmental allergen
Triad of atopy?
Eczema
Asthma
Hay fever
Allergy onset
Infancy
Atopic dermatitis
Food allergy (milk, eggs, nuts)
Allergy onset
Childhood
Asthma
Allergic rhinitis
Allergy onset
Adults
Drug
Bee
Oral allergy syndrome
Occupational allergy
Pathology in atopic dermatitis?
Defects in beta defensin predisposing to staph aureus superinfection
Irritants in atopic dermatitis
Irritants, food, environmental
Treatment of atopic dermatitis
Emollients
Skin oils
Topical steroids
PUVA
Phototherapy
IgE mediated food allergy
Anaphylaxis
Cell-mediated food allergy
Coeliac
IgE/cell-mediated allergy
Atopic dermatitis
Dx of food allergy
Food diary
Skin prick tests
RAST
Challenge tests
Resolve by adulthood
Mx of food allergy
Dietician, food avoidance, epipen
Control asthma if present
Common allergens in food allergy?
Milk
Egg
Peanut
Shellfish
Fish
Tree nut
Oral allergy snydrome
Exposure to allergen induces food allergy
Symptoms limited to mouth;
2% get anaphylaxis
Allergens in OAS
Birch pollen + Rosacea fruit
Ragweed +Melons
Mugwort + celery
Mx of OAS
Avoid food
If ingested wash mouth and take antihistamine
Allergens in latex food syndrome
Chestnut
Avocado
Banana
Potato
Tomato
Kiwi
Papaya
Eggplant
Mango
Wheat
Melon
Pathology in latex food syndrome
Some foods have latex like components and hence latex allergy sufferers will also have food allergies
Dx of LFS
Skin prick
Allergens in allergic rhinitis?
Seasonal (tree and grass pollen, fungal spores)
Perennial (pets, house dust mite)
Occupational (latex, lab animals)
Symptoms of allergic rhinitis
Nasal itch and obstruction
Sneezing
Anosmia
Eye symptoms
RAST test
A radioallergosorbent test (RAST) is a blood test used to determine the substances a subject is allergic to. This is different from a skin allergy test, which determines allergy by the reaction of a person’s skin to different substances.
Dx of allergic rhinitis
Pale bluish swollen nasal mucosa
Skin prick
RAST
Mx of allergic rhinitis?
Allergen avoidance
Anti-histamine
Steroid nasal spray
Sodium cromoglycate eye drops
Oral steroids
Ipratropium nasal spray
Grass pollen desensitisation
Allergen in acute urticaria?
50% idiopathic
50% caused by food, drugs, latex, viral infectyions and febrile illnesses
Pathology of acute urticaria
IgE-mediated reaciton
Wheals which resolve within 6w
Def: anaphylaxis
A severe systemic alelrgic reaciton: respiratory difficulty and hypotension
What are the mechanisms of anaphylaxis?
Can be IgE mediated: peanut, penicllin, wasp or bee venom, latex
Or
Non-IgE mediated: aspirin and NSAIDs, IV contrast media, opiod analgesia, exercise
Dx of anaphylaxis
Serum typtase
Concentration proportional to fall in BP, rises to peak 60 mins after exposure
Mx of anaphylaxis
ABC:
Lift legs to boost venous return
100% O2
Inhaled bronchodilators: salbutaoml
IM adrenaline 500mg
IV hydrocortisone 100mg
IV Chlorphenamine 10mg
IV flyuds
Seek help
Clinical picture in IgE allergic response
Angioedema, urticarial, rhinoconjuncitvitis, wheeze, D+V and vomiting
Clinical picture in non-IgE mediated response
Recurrent abdo pain
Diarrhoea
Fatigue
Migraine
Hyperactivity
Depressoin
Confusion
Skin prick test=
Gold standard
Local wheal
Positive control- histamine
Negative cointrol- diluent
No antihistamines in 48h before hand
Diagnostic tests in allergy
Skin prick
RAST
Component allergen specific IgE
Challenge test
Features of challenge test
Challenge test: medically supervised exposure. Gold standard for food allergy diagnosis. Increasing volumes of the
allergen are ingested. Double blind placebo or open challenge. Expensive in terms of staff clinical time. Risk of severe
reaction
What is component allergen specific IgE testing?
Component Allergen Specific IgE: measures response to a specific allergen related protein. E.g. peanut has 5 major
allergens. Useful for clinical information to severity if given a whole peanut.
Peanut: Ara h 2: anaphylaxis risk to peanut and nuts
Ara h 8: localised oral reaction to peanuts and stone fruits only.
Ara H2
Anaphylaxis risk to peanuts and nuts
Ara H8
Localised oral reaciton to peanuts and stone fruits onlyq
What is an important risk factor for atopic dermatitis?
Filaggrin mutation
Fillagrin
Structural protein which maintains the integrity of the epithelial barrier and contributes to skin hydration
LOF mutation found in atopic dermatitis.
Immunosuppressant treatment options for atopic dermatitis
Topical steroids
Cyclosporin
Tacrolimus
What are the different types of food “allergy”
Intolerance
Aversion
Allergy: IgE mediated
AEG?
Allergic eosinophilic gastroenteritis
IgE/cell-mediated food allergy
Pathophysiology of chronic urticaria
>6w persistent itchy wheals
Idiopathic or autoimmune (IgG against Fc epislone R1 or IgG against IgE) or phyzical
Mx of chronic urticaria
Doxepin: TCA and anxiolytic
Ciclosporin for refractory cases
Pathophysiology of Hereditary angioedema
C1 inhibitor deficiency (C1 inhibitor inhibits the complement systm)
Deficiency of C1 inhibitor allows plasma kallikrein activaiton leading to the production of bradykinin
Symptoms of Hereditary angioedema
Angioedema can occur with mild trauma or spontaneously
Considerations for hereditary angioedema
Can predispose to SLE due to consumptive effect on complement C3 and 4
What are the constitutive barriesr to infection?
Skin
Mucosal surfaces
Commensal bacteria
What are the features of skin that provide a barrier to infection
Tightly packed keratinised cells
Low pH and O2 tension
Sebaceous glands which produce: hydrophobic oils that repel MO and water
Lysozyme which destroys the structural integrity of the cell wall
Ammonia and defnesins which have antibacterial properties
