Core Immunology Flashcards

Question

How do you diagnose allergies?

Answer 1

* History * Specific IgE (>0.35 KuA/L)- TIME duration before symptoms * Skin prick test (>3mm wheal)- put drop of allergen extract on skin, scratch skin & will see weal & flare response * Intra-dermal test- (more invasive) inject allergen into intra-dermal space, see if size of bleb (mark you made when you have injected) increases * Oral challenge test – Gold standard- take 1/8th of a peanut & keep doubling dose- see if they can tolerate 4 or 5 peanuts (if can not allergic) * Basophil activation test- see if basophils change in surface proteins * Component resolved diagnostics * Immediate onset reacs- type 1 happens in few mins * Can measure specific antigens to common allergens- In vitro test (take blood sample form patient) * Take blood to see if antibodies against them- if are against parts of protin that are more stable- more severe reac

Answer 2

Principle of the basophil activation assay; • Upon cross-linking of membrane-bound IgE, basophils upregulate expression of specific activation markers e.g.CD63, CD203c & expression of the inhibitory receptor CD300a • Exact mechanisms causing basophil degranulation remain elusive, but phosphorylation of p38 MAPK pivotal role in cell activation • Put allergen on basophil

Answer 3

Advantages: Safe Disadvantages: False negatives, False positives

Answer 4

Advantages: Quick, Patient satisfaction Disadvantages: False negatives, False positives, Antihistamines, Slight risk

Answer 5

• Symptomatic o Antihistamines, Steroids, Adrenaline (if severe life threatening reac- patients can carry these if reac can affect airways) o Specific – Immunotherapy (Subcutaneous or Sublingual) • Indications o Life threatening reactions to Wasp & Bee sting o Severe Hay fever o Animal dander allergy • Not helpful o Multiple allergies don’t respond to immunotherapy as well o Food allergy o Allergic rashes – Eczema, Urticaria

Answer 6

* Allergen-specific immunotherapy (SIT) improves quality of life of treated individuals & reduces symptoms of allergy & medication use. * SIT; improved tolerance to allergen challenge, ↓ in immediate-phase and late-phase allergic inflamm, prevents development of new allergic sensitizations & ↓ progression of allergic rhinitis to asthma. * SIT is disease modifying & duration of effect beyond the treatment period. * SIT modifies cellular & humoral responses to allergen; ratio of T helper 1 (TH1) cytokines to TH2 cytokines increased & functional regulatory T cells induced. * Interleukin-10 (IL-10) produc by monocytes, macrophages, B cells & T cells is increased * The expression of transforming growth factor- (TGF) is increased & (with IL-10) TGF might contrib to regulatory T-cell function & immunoglobulin class switching to IgA, IgG1 and IgG4. * These immunoglobulins compete with IgE for allergen binding, decreasing allergen capture & presentation by IgE in complex with high-affinity recep for IgE (FcRI) or low-affinity recep for IgE (FcRII). * SIT also reduces mast cells and their ability to release mediators. * Eosinophils and neutrophils recruitment to sites of allergen exposure is also reduced

Answer 7

• Major Food Allergens (if person thinks allergic to something go through list on this slide); o Water soluble glycoproteins 10 - 60 kd o COW’S MILK (more common in childhood- 80% don’t end up with this allergy) o EGG o LEGUMES – PEANUT (if in childhood usully don’t always have this allergy when older) ; SOYBEAN; TREE NUTS o FISH o CRUSTACEANS / MOLLUSCS o CEREAL GRAINS (refrain from testing to wheat as the wheat specific IG often +ve) • Common- food intolerance rather than food allergy • Pharmacological effect of food not allergic reac e.g. heart beats faster after coffeee • Lactose intolerance- lack lactose recep • Allergies; can get allergy syndrome (e.g. eat fresh apple- react, but don’t reac to cooked apple as proteins more sensitive, & when gets to stomach acid breaks protein down so don’t get reaction below airways)

Answer 8

* Gastrointestinal: vomiting, diarrhoea, oral symptoms * Respiratory (upper & lower): rhinitis, bronchospasm * Cutaneous: urticaria, angioedema, role of food in atopic dermatitis unclear (rash for 2-3 wks unlikley is down to IgE sensitivity) * Anaphylaxis

Answer 9

* Cytotoxic- type II; hapten binds to protein on RBC- this combo recognised by immune system= haemolytic anaemia * If no response to eczema treatment creams- patch test them to see what allergic to * Chugg Strauss syndrome (serious)- don’t try testing them just tell them to avoid that drug ``` History Indication for the drug Detailed description of the reaction Time between drug intake and onset of symptoms Number of doses taken before onset ``` Management Intradermal testing Graded challenge Desensitization

Answer 10

* Inflammation in target tissues (cells in tissues- respond to pathogens) * Cells; macrophages, dendritic cells, mast cells, neutrophils, complement * Pattern recognition against broad classes of antigen * No memory * No amplification * Little regulation * Fast response (hours – days) * Short duration

Answer 11

* Cells circ through blood & coordinate responses * Cells; T & B cells * Highly specific (T and B cell receptors)- learn antigens that are foreign or not (memory) * Strong memory and amplification component (e.g. vaccines, previous infection) * Many regulatory mechanisms * Slow response (days to weeks for initial exposure) * Responses may last months - years

Answer 12

* Dendritic cells (innate) present antigen to T cells (adaptive) * T cell cytokines & B cell antibodies activate innate cells to cause inflammation * Innate immunity doesn’t adapt as well as adaptive immune system * Macrophage presents to T cell then get adaptive response * When T/b cells recognise foreign- they also active immune response (don’t work on their own)

Answer 13

* Neutrophils: eat and destroy pathogens (netosis- pus) * Macrophages: also produce chemokines to attract other immune cells * Dendritic cells (phagocytic): also present antigen to adaptive immune system

Answer 14

* Mast cells, basophils, eosinophils: produce histamine and other chemokines and cytokines * Vasodilatation, attract other immune cells * Defence against parasites, wound healing but also allergy and anaphylaxis

Answer 15

* Directly attacks pathogens via alternative and lectin pathways * May be activated by adaptive immune system via antibodies

Answer 16

Signal between different immune cells (e.g. innate to adaptive, adaptive to innate)

Answer 17

Attract other immune cells to sites of inflammation (rather than signal)

Answer 18

• = the ADAPTIVE immune system (learned response to antigen) recognises and targets the body’s own molecules, cells and tissues (instead of infectious agents and malignant cells) • Main characteristics: o T & B cells that recognise self antigens o B cells and plasma cells that make autoantibodies against self antigens o Inflammation in target cells, tissues and organs is secondary to actions of T cells, B cells and autoantibodies • Autoimmunity is more about the learning of what is self & non-self Immunological disruption: Adaptive immunity Main cellular involvement: B and T cells Antibody involvement: Autoantibodies present Clinical features: Continuous progression Conceptual understanding: Breaking of self-tolerance Main genetic susceptibility: MHC class II associations and adaptive response genes Therapy: Anti-B and T cell Examples: Monogenic ALPS and IPEX, Polygenic RA and SLE Autoimmunity • Theoretical concept • Many cells of the immune system have capacity for autoimmune functions • Overlap with normal immune functions such as anti-tumour immunity Autoimmune Disease • Distinct clinical entities • Breakdown of self-tolerance • Environmental factors acting on favorable genetic background • Wide variety of pathogenic mechanisms between diseases

Answer 19

• To distinguish from autoimmune diseases • Main characteristics: o seemingly spontaneous attacks of systemic inflammation (not learned T & B response) o no demonstrable source of infection as precipitating cause o absence of high-titre autoantibodies and antigen specific autoreactive T cells o No evidence of auto-antigenic exposure Immunological disruption: Innate Immunity Main cellular involvement: Neutrophils, macrophages Antibody involvement: Few or no autoantibodies Clinical features: Recurrent, often seemingly unprovoked attacks Conceptual understanding: Tissue-specific factors/danger signals Main genetic susceptibility: Cytokine and bacterial sensing pathways Therapy: Anti-cytokine (IL-1, TNF, IL-6) Examples Monogenic hereditary periodic fevers, polygenic Crohn’s disease, spondylarthropathies

Answer 20

* Genes can pre-dispose to certain disease e.g. certain MHC pre-disposes to rheumatoids but not just this as not born with disease * Env trigger acts on genetic background to cause disease * Immune regulation- certain regulation to help stop disease e.g. autoimmnity normally stops cancer (wipes out mutated cells before cause cancer) (regulation component can go wrong)

Answer 21

• Have central & peripheral types of tolerance • Central tolerance; o B cells- Bone marrow o T cells- Thymus • T cells in thymus as develop- get a T cell recep (recognises antigen- has variability; can recognise anything e.g. pathogen or self antigen), then process of –ve selection (tested against self-antigens, if recep picks up antigen delete it), then +ve selection for useful T cells (e.g. if recep doesn’t recognise self- is +vly selected) • T cell can be useful if only recognise at low level- regulatory • B cells go through similar process in bone marrow

Answer 22

``` Class II MHC Genes May Shape T Cell Repertoire: Predisposing to Autoimmunity • B cells & T cells variety to receptors they can express (not genetically linked) but can inherit types of molecules that leads to getting you autoimmune disease • MHC class I (on all nucleated cells in body- function is if there is something inside that tissue cells e.g. virus, gets presented on that surface) encoded by genes in HLA-A, HLA-B, HLA-C, On all nucleated cells, Presents antigen to CD8+ T cells • MHC class II (APCs e.g. skin infections, dendritic cell eats up antigen & takes it to lymph node to present to T cell in MHC) encoded by genes in HLA-DP, HLA-DQ, HLA-DR, On dedicated APCs, Presents antigen to CD4+ T cells • Have finite number of MHC types; each MHC subtype presents a certain antigen better than others e.g. if have a certain type of MHC might present self antigen better to T cells autoimmune (so usually have MHC class II association) ```

Answer 23

FOXP3 mutation (gives regulatory cells)- failure to develop regulatory T cells – severe autoimmunity from birth

Answer 24

o PTPN22 mutations (genes that control how rapid activated T cells response is (how effective T cells are)- cause T cells to be activated more easily – stronger immune response in general

Answer 25

• Sex (hormonal influence)- women >> men • Age- autoimmunity more common in elderly (more exposed to diff env pathogen more likely to get autoimm disease) • Sequestered Antigents o May be recognised as foreign by the immune system (e.g. cell nucleus, eye, testis) o Immune doesn’t react to certain cells as immune system never exposed to them so if happen to get exposed to them= autoimm • Environmental triggers o Infection o Trauma-tissue damage o smoking

Answer 26

• Molecular mimicry e.g. in rheumatic fever antibodies against M protein of Streptococcus also happen to react against the glycoproteins of the heart valve cells (recep just happens to fit)

Answer 27

* Citrullination of proteins make them more immunogenic (=rheumatoid arthritis) * Self antigens start to be recognised as foreign as antigen itself changed- a.a. citrulline not encoded into genome so will never make it in protein but can sometimes switch places with arginine (which was coded- what smoking does)- makes protein look a bit foreign to body * Tissue transglutamase alters gluten to help it bind to HLA-DQ (=coeliac disease) * Failure to clear apoptotic debris increases availability of sequestered antigens inside the cell (=systemic lupus erythamatosus)

Answer 28

• Th cell need antigen presented to them by APC with MHC • T cell when sees antigen can; o Differentiate into Th1 cell- make cytokines (signal to macrophages which make loads more cytokines)= inflammation o Differentiate into Th2 cells= talk to B cells (cross talk) • B cells differentiate into memory B cells & plasma cells= autoantibodies & cytokines=inflammation • For process to stop; usually get rid of whatever causing it (e.g. infection)- but can’t do this in autoimmune disease (unless regulation) Macrophages release inflammatory cytokines, this is also stimulated by T cells: APC binds to Th cell which causes Th1 to release inflammatory cytokines and Th2 to activate B cells causing auto antibody production

Answer 29

• Autoreactive B cells and autoantibodies o Directly cytotoxic o Activation of complement o Interfere with normal physiological function • Autoreactive T cells o Directly cytotoxic o Inflammatory cytokine production • General inflammation and end-organ damage

Answer 30

Organ Specific: • Affect a single organ • Autoimmunity restricted to autoantigens of that organ • Overlap with other organ specific diseases • Autoimmune thyroid disease is typical Systemic • Affect several organs simultaneously • Autoimmunity associated with autoantigens found in most cells of body • Overlap with other non-organ specific diseases • Connective tissue diseases are typical

Answer 31

* More than 100 different diseases * Can affect any organ of body * Onset in middle age, old age * More common common in the elderly and women * Leads to loss of organ function * Lifelong-chronic condition * Characteristic exacerbation and remission * Traditionally divided into organ specific or systemic * Common for diseases to overlap

Answer 32

• Hashimotos thyroiditis (underactive thyroid) o Destruction of thyroid follicles by autoimmune process o Associated with autoantibodies (only in thyroid gland) to thyroglobulin & to thyroid peroxidase o Leads to hypothyrodism o 1st get hypEr as lots of thyroxine released but end up with hypo o Inflamm & damage • Grave’s disease o Antibody mimics TSH- binds to TSH recep on thyroid galnd which stimulates recep which makes gland over active o Inappropriate stimulation of thyroid gland by anti-TSH-autoantibody o Leads to hyperthyroidism o Graves- just antibody causes disease

Answer 33

* Acetylcholine usually stimulatess muscle contraction * Myasthenia gravis- antibody against ACh receptors these antibodies block receptors so no acetylcholine stimulation therefore patients have decreased muscle activity

Answer 34

• Can’t absorb B12- as intrinsic factor can’t bind it as autoantibody blocks intrinsic factor (withoit binding to intrinsic factor Vit B12 cant be absorbed) , can get parathesia , fatigue

Answer 35

* Antinuclear antibodies against structures in cell nucleus=systemic autoimmune disease as cell nucleus everywhere in body * Reason for butterfly rash- when go out in sun, UV light causes cells to undergo apoptosis, breaks down & contents of cell on outside of cell (in bleb), so the nuclear antigen visible to immune system (no longer hidden in cell) * Non-organ specific- autoantibodies against antigens in the nuclus combine with their targets forming immune complexes in the circulation these can land anywhere in body (not necessarily where antigen came from e.g. skin) so can cause inflammation anywhere that’s why things like renal problems are a common side effect

Answer 36

* Systemic lupus erythematosus * Scleroderma * Polymyositis * Sjogrens syndrome

Answer 37

* Should use diagnostic tests to answer specific questions/ support clinical diagnosis NOT as screening tools * Need to have an idea of what your testing for before ordering diagnostic test * Their ability to correctly discriminate between health & disease is improved when they are used in the appropriate population

Answer 38

A: test positive and disease positive B: test positive and disease negative C: test negative and disease positive D: test negative and disease negative * Sensitivity [a/(a+c)]- True positive: how good the test is in identifying people WITH the disease (ability to pick up affected individuals) * Specificity [d/(c+d)]- True negative: meausure of how good the test is in correctly defining people WITHOUT the disease * Low specificity if test also picking up people without disease * Positive predictive value [a/(a+b)]-The proportion of people with a positive test who have the target disorder * Negative predictive value [d/(c+d)]- The proportion of people with a negative test who do not have the target disorder.

Answer 39

* Non specific- Inflammatory markers | * Disease specific- Autoantibody testing, HLA typing

Answer 40

* ESR * CRP- acute phase response * Ferritin- acute phase response protein (high) * Fibrinogen- acute phase response protein * Haptoglobin * Albumin * Complement (e.g. serum C3 or 4- e.g. systemic autoimm disease- low complement= active episode) * Can get +ve blood test indicating lupus- doesn’t mean is active disease * Need other investigations to guide decision & assessment of patient * Inflamm markers & complementary tests- in someone to determine if active disease

Answer 41

Antibodies in the patient’s blood that bind to the cell nucleus- can be then more specific and identify subtypes of antibody that bind to different bits of the cell nucleus Sensitivity & Specificity of Specific Anti-Nuclear Antibodies • Can find ANA in people that had just had illness, can find ANA in older people (aging immune system), or ANA in an autoimmune illness to come (but don’t mean anthing at that moment in time) • So can’t just look at ANA on it’s own

Answer 42

* Detect autoantibodies; put cells of interest on microscope slide, use fibroblasts (large nuclei to see- will have more of antigens in them), then incubate slides with patient serum, , if have autoantibodies in patients serum auto-Abs will stick to antigens on cells, use antiIgG against Auto-Abs which are fluorescently labelled * Nuclei flouresence * If have autoantibodies in patients serum auto-Ab will stick to antigen on cells * Antihuman Igg * Pattern on nucleus (e.g. homogenous, speckled etc) depends on specific target antigen

Answer 43

``` Techniques; • Anti-dsDNA o Crithidia luciliae assay (protosoa) o Farr assay o ELISA • ENA’s o Immunoblots o Individual ELISA’s o Combination of antigens • >100 different antibodies described in SLE • Look for more specific targets • Smash up nucleus & smear nuclear material across paper, will see molecular mass of certain proteins that will be seen on block, use 2ndry antibody to detect ```

Answer 44

* Attach beads to antigens of interest (know what targets are)- beads have flouresence that you can detect using lasers * If have something attached to bead 2ndry antibody seen in diff colour * Incubate serum with beads, if have mulitple autoantibodies attach to their specific beads * Need to interpret info in clinical context * Disadv- looking for normal autoantigens (occasionally patients with +ve test which is non-specific)

Answer 45

``` Ro: neonatal/ Sjorens syndrome dsDNA and Sm, RNP etc: SLE La: Sjorens syndrome, SLE CCP: Rheumatoid Athritis Scleroderma: ANA positive for Scl 70 Antibody ```

Answer 46

* RF is an antibody (IgM, IgG or IgA) directed against the Fc portion of IgG * Commonly found in rheumatoid arthritis but NOT diagnostic of the diseases (sensitivity & specificity around 70%- as RF can come after infection, RF physiological role to mop up unnecessary antibodies in blood) * RF can be seen with other diseases in which polyclonal stim of B cells is seen (e.g. chronic infections) * High titters may be pathogenic in vasculitis (high levels of RF sticky protein- forms complexes- can precipitate out of circulation= stick to vessel wall=activate complement=vasculitis) * Common test for autoimmune condition * Can auto aggregate

Answer 47

* ACPA more specific (95%) for rheumatoid arthritis then Rheumatoid Factor * Similar sensitivity to RF but more specific * Useful prognostic marker * ACPA positive patients tend to have more severe and erosive disease * If patient has citrulated antibodies- more aggressive disease

Answer 48

 The diagnosis of Rheumatoid Arthritis is clinical  Combination of symptoms, Xrays, blood tests  High RhF, CCP and elevated ESR and CRP add to the probability of a definitive diagnosis  Early treatment can prevent joint damage and significant morbidity.

Answer 49

Ordered when ?vaculitis- e.g. renal or ENT • Incubate neutrophils with patients serum, use 2nsry autoantibodies to see what attached to neutrophils ANCA is the pattern and anti-PR3/MPO is the autoantibody causing the pattern Cytoplasmic (c)ANCA: Granular fluorescence of neutrophil cytoplasm with nuclear sparing. Target antigens: PR3 (90%) and MPO Perinuclear (p)ANCA: Apparent fluorescence of the nucleus only: Target antigens: MPO (70%) and PR3

Answer 50

Histology: Leukocytoklastic vasculitis; necrotising, granulomatous inflammation Ear, Nose, Throat: Nasal septum perforation, saddle-nose deformity, conductive or sensorineural hearing loss, subglottic stenosis Eye: Orbital pseudotumours, scleritis, episcleritis, uveitis (50%) Lung: Nodules, infiltrates, or cavitary lesions, alveoral haemorrhage Kidney: Segmental necrotising glomerulonephritis Heart: Occasional valvular lesion Peripheral nerves: Vasculitic neuropathy (10%) Eosinophilia : Mild eosinophilia occasionally

Answer 51

* How good it is to predict certain conditions * Can’t rely entirely on autoantibody for diagnosis (this is to support diagnosis) * Positive ANCA is extremely useful in suggesting the diagnosis in the proper clinical setting * Histopathology remains the gold standard for diagnosis in most cases (e.g. if renal or cardio involvement) * Negative ANCA assays do not exclude AASV (vasculitis) since 10%-50% of patients may be ANCA neg * Persistence of ANCA in the absence of clinical indications of active disease does not indicate a need for continued treatment (see how succesful treatment is) • Reemergence of ANCA pos in a patient who was ANCA neg whilst in remission suggests a risk of disease flare. The temporal correlation between the return of ANCA and a disease flare is poor WG: 80%-90% ANCA positivity and PR3>>MPO 75%-90%:5%-20% ANCA Antigen specificity MP: 70% ANCA positivity and PR3>>MPO 50%-80%:10%-25% ANCA Antigen specificity CSS: 50% ANCA positivity and PR3>>MPO 2%-50%:3%-35% ANCA Antigen specificity

Answer 52

* Anti-mitochondrial Ab specific for primary biliary sclerosis * Anti-smooth muscle and anti-liver/kidney/microsomal (LKS) Abs, found in autoimmune hepatitis * These antibodies (above) can be present before disease presents * Antibodies detected by IF screening using rodent tissue block (oesophagus, liver and kidney) and antigen specific ELISA * Use tissue block ; bits of kidney, liver, stomach- depending on immunoflouresence get can predict specific autoantibodies relevant to autoimmune liver disease

Answer 53

``` • Non-pathogenic • Several types: o islet cell antibodies o anti-GAD65 anti-GAD67 o anti-insulinoma antigen 2 (IA-2) o insulin autoantibodies (IAAs) • Disappear with progression of disease and total destruction of β islet cells • Type 1 autoimm diabetes- autoimm antibodies against islet cells in pancreas=what sort of antibodies developed e.g. 1 type in circulation or can have wide spread (shows disease progressing- have established type 1 diabetes, so to try prevent coming to this point can try use markers to help put in place intervention) ``` Role of Autoantibodies in Diagnosis of Type I DM • Disease conformation • to identify relatives and patients at risk of developing autoimmune diabetes • Negative predictive value of ICA and IAA is almost 99% • Increased risk of disease development with greater n.o. of diff autoantibodies present & younger age

Answer 54

* Cytokines determination in serum * Detection of antigen specific autoimmune T and B cells * T-reg detection, ? measure of therapeutic response * Personalised medicine, genetic profiling to determine individual risk of the disease and to tailor the most appropriate therapy * Discovering increasing number of biomarkers some more useful than others

Answer 55

Clinical situations where the immune system is not effective enough to protect the body against infection • Primary- inherent defect in immune system (usually genetic) e.g. component may not be working, usually severe • Secondary- immune system affected due to external causes e.g. HIV infec

Answer 56

* Breakdown in physical barriers: CYSTIC FIBROSIS (defect in mucous in resp tract) * Protein loss (when loose proteins e.g. Igs can’t remake enough or can loose proteins e.g. by weeing them out (kidneys))- burns, protein loosing enteropathy, malnutrition * Malignancy- especially lymphoproliferative disease, myeloma (cancer of plasma cells- take up all the space in bone marrow so not enough space for other cells) * Drugs- steroids, DMARDS (disease modifying anti-rheumatic drugs e.g. methotrexate), Rituximb (mono-clonal antibody- used clinically to try to eradicate cells e.g. can use in rheumatoids), anti-convultants, myelosuppresisve (treat leaukaemias- kills good & bad cells so get immunodeficiency) * Infection- HIV, TB

Answer 57

* Neutrophils, macrophages * Eat bacteria/ fungi= destroys them * Bacterial infection= neutrophils (e.g. in chest infec green sputum- neutrophils, if white- tends to be a viral infec) * Macrophages in tissues (monocytes in blood)- start local inflamm response * In macrophage (lysosome & phagosome fuse)

Answer 58

• Pathogen recognition receptors (PRRs)- recognise conserved pathogen associated molecular patterns (PAMPs) (unique to each pathogen) e.g. lipopolysaccharide • Phagocytes use PRRs to detect pathogens • Toll like receptors- a type of PRR; o TLR3- recognises viral RNA (defects in TLR3 lead to recurrent HSV encephalitis) o TLR4- recognises lipopolysaccharide (on lots of bacteria) o TLR5- recognises flagellin (makes up flagella on bacteria) • Cascade of events when receptor triggered with intracellular molecules= production of inflammatory cytokines • MyD88 & IRAK4 are involved in this cascade

Answer 59

a type of Pattern Recognition Receptor

Answer 60

recognises viral RNA (defects in TLR3 lead to recurrent HSV encephalitis)

Answer 61

recognises lipopolysaccharide (on lots of bacteria)

Answer 62

recognises flagellin (makes up flagella on bacteria)

Answer 63

* Cascade of events when receptor triggered with intracellular molecules= production of inflammatory cytokines * MyD88 & IRAK4 are involved in this cascade

Answer 64

IRAK4 DEFICIENCY • Clinical presentation; o Recurrent bacterial infection (especially strep & staph)- pneumonia, meningitis, arthritis o Poor inflammatory response (person with pneumonia should have raised CRP but because cascade broken they don’t have raised CRP) o Susceptibility to infection decreases with age • Rx; prophylactic antibiotics, IV immunoglobulin if severe MyD88 presents similarly

Answer 65

* Inside phagocyte * NADPH complex- several proteins stuck together including gp91phox. This complex makes electrons which bind to O2- to form hypochlorus acid production * This kills bacteria

Answer 66

* Granulomas- collection of macrophages * Defect in gp91phox * Macrophage sees bacteria but can’t do anything, so calls more macrophages but they can’t do anything- end up with collection of macrophages Typical presentation History of recurrent skin abscesses, 1 x previous pneumonia Presented to hospital with a liver abscesses Mothers brother-similar but milder symptoms Investigations: Normal immunoglobulins, lymphocytes and neutrophil count

Answer 67

* Recurrent abscesses; lung, liver, bone, skin, gut * Unusual organisms; staphylococcus, Klebsiella, serretia, Aspergillus, Fungi * Rx; haemopoetic stem cell transplant, antibiotics * Tests rely on REDUCTION (gain of electron) * Get patient’s neutrophils & activate them- then measure how many neutrophils reduce dihydrorhodamine * Measure Dihydrorhodamine reduction using flow cytometry * Nitro blue tetrazolium (NBT) dye reduction- healthy neutrophils should go purple (NBT reduced)

Answer 68

Non immunoglobulin proteins, that are important in the immune system for Cell lysis (kill invading bacterium) Control of inflammation Stimulate phagocytosis Sequence of events activates complement proteins • Classical pathway- bacteria (c1 antigen antibody= cascade) • MBL pathway similar to classical pathway (but mannose binding lectin acitaves cascade) • Sequence of events activates complement proteins o C3a, C4a & C5a- arteriole dilation, histamine release form mast cells, chemotaxis of phagocytes o C3b- microbe opsonisation promotes phagocytosis o C5b, C6, C7, C8, C9- form MAC (causes microbe cytolysis- punches holes in it) • C5b binds C6 & 7= C5b67 complexes bind to memb via C7= c8 binds to complex & inserts into cell memb of pathogen= C9 bind to complex & polymerise=1-16 molecules of C9 bind to form a pore in the memb

Answer 69

* Lyse foreign cells that are covered in antibody * Test; antigen RBC & antibodies against RBC (of sheep), drop on patients serum & if MAC working RBCs should lyse)- this test looks at all components to see if working

Answer 70

SLE, infections, myositis

Answer 71

* C5-9 (forms memb attack complex)- repeated episodes of BACTERIAL meningitis (particularly Neisseria meningitis * if get more than one bacterial meningitis- THIS IS NOT NORMAL

Answer 72

* Neutralisation (blocks viral binding sites/ coats bacteria) * Agglutination of bacteria * Percipitation of dissolved antigens * Or activation of complement

Answer 73

* Defect in Bruton’s Tyrosine Kinase (BTK)- need for B cell signalling & maturation * BTK DOWNSTREAM of B cell recep so if this blocked B cell can’t respond- this happens in the the bone marrow so B cells don’t mature downstream so may not have any mature B cells * B cell maturation NOT completed in bone marrow

Answer 74

Male presented before age of 5; 3 hospital pneumonia admissions, recurrent chest infecs in between, sinusitis. Mother’s brother passed away age 35 from bronchiectasis (suggetss x linked recessive). • Bloods; o No B cells, normal T cells o No IgG, IgA, IgM o CT: bronchial thickening, evidence of recent pneumonia

Answer 75

* CVID (common variable immunodeficiency) – low IgG, IgM, IgA * IgA deficiency– is found in entry of mucosal surfaces * X-linked hyper IgM syndrome (1st antibody B cells if IgM then G (which is better) then A)- cell machinary can’t switch to making other Igs so have lots of M but noth much IgG or A * Transient hypogammaglobulinaemia of infancy (4-6mnths antibodies should usually be produced) * Loss of antibody secretion * Usually leads to recurrent bacterial infec with pyogenic organisms (bacteria that cause pus) * Treat with antibiotics then IV IgG for life * Most very serious * Some less serious e.g. IgA deficiency; 1 in 5-700, some completely well, higher risk of autoimmune disease e.g. coeliac

Answer 76

50 yr old female, rheumatoid arthritis history (severe), no infecs most of adult life but 2 yr history of recurrent bacterial chest infecs (5 courses of antibiotics in winter). PMH: asthma. Drug Hx: currently on methotrexate & infliximab, previously rounds on Rituximab. Has also had gold, sulfasalzine in past. • Not likley to be genetic defect or would have had lots of infecs before too • Ix (investigations): slightly low B & T cells, low IgG & IgA Has secondary antibody deficiency due to drugs (comparatively common)- as drugs she’s on depress immune system • Knocks out B cell so eventually also get lower plasma cells • Others affect T cells Treatment: • Antibiotics • Immunoglobulin G replacement (as IgG makes up most of blood, IgM lower & A usually in secretion) • Can give it IV or subcutaneously

Answer 77

SCID (Severe Combined Immunodeficiency) • Diagnosis: no T cells & suggestive history • Investigations; o Normal IgG levels, NO IgA, reduced IgM o Lymphocyte makers show absent/ reduced T & NK cells but present B cells • RX: o Peadiatric emergency o Antibiotics, antivirals, antifungals o Asepsis o Haemopioetic stem cell transplant (only cure) o Screen • SCID casues; o Defect/ absence of critical T cell molecule (TCR, coomon gamma chain) o Loss of communication- MHCII deficiency (T cells can’t help B cells so pretty non functional) o Metabolic- adenosine deaminase deficiency (also have bone deformities & neurological defects) Presentation may be a baby with fulminant chicken mix and recurrent infections (often consanguineous parents) Defects in T Cells • (If pateint had no T cells- PAEDIATRIC EMERGENCY) • Usually more severe as B cells also need T cell help (so even if tehre are B cells they don’t function) • Symptoms; recurrent infec with opportunistic infections, bacteria, viruses • Fungi (candida), protozoa (pneumocystis) • Types; o SCID o Others e.g. DOCK8 deficiency (B & T cells can’t communicate)

Answer 78

* Immunomodulation- Using immunomodulatory drugs to manipulate the immune system to get the desired immune response * A therapeutic effect of immunomodulation may lead to immunopotentiation, immunosuppression, or induction of immunological tolerance

Answer 79

* Immunization * Replacement therapy * Immune stimulants or suppressants * Anti-inflammatory agents * Allergen immunotherapy (desentization) * Adoptive immunotherapy

Answer 80

Definition Medicinal products produced using molecular biology techniques including recombinant DNA technology Main classes Substances that are (nearly) identical to the body's own key signaling proteins Monoclonal antibodies- •Used in rheumatoids • Anti-TNF drugs e.g. Infliximab (but has murine variable domain- own immune response against it so ineffective) • Cetrolizumab- just has Fab region with chain for stability Fusion proteins- Entercept

Answer 81

* Immunopotentiation- enhancement of immune response by increasing it’s speed, extent & duration * Immunization; passive or active * Replacement therapies * Immune stimulants

Answer 82

• Definition: transfer of specific, high-titre antibody from donor to recipient. Provides immediate but transient protection • Problems: o Risk of transmission of viruses o Serum sickness • Types: o Pooled specific human immunoglobulin o Animal sera (antitoxins an antivenins)- animals injected with toxin, have antibody response • Uses: o Hep B prophylaxis and treatment o Botulism, VZV (pregnancy), diphtheria, snake bites

Answer 83

``` • Definition: to stim development of a protective immune response & immunological memory • Immunogenic material: o Weakened forms of pathogens o Killed inactivated pathogens o Purified materials (proteins, DNA) o Adjuvants • Problems: o Allergy to any vaccine component o Limited usefulness in immunocompromised (either don’t respond to vaccine/ risk of having the infection) o Delay in achieving protection ```

Answer 84

* Pooled human immunoglobulin (IV or SC)- used in RX of antibody deficiency states * From blood donors; plasma fractionation, keep immunoglobulins * G-CSF/GM-CSF- act on bone marrow to increase production of mature neutrophils * IL-2 (Stimulates T cell activation- rarely used as IL-2 used in regulatory cells more so IL2 may be better used in autoimmune conditions) * α-interferon (Main use in treatment of Hep C) * β-interferon (Used in therapy of Multiple Sclerosis) * γ-interferon- certain intracell infecs e.g. salmonella (atypical mycobacteria), chronic granulomatous disease & IL-12 def

Answer 85

* Cortocosteroids * Cytotoxic/ agents * Anti-proliferative/activation agents * DMARD’s (disease modifying anti-rheumatic drugs) * Biologic DMARD’s

Answer 86

* Can suppress innate & adaptive immune systems (not very specific effect) * Decreased neutrophil margination (so neutrophil count will go up) * Reduced production of inflammatory cytokines * Inhibition phospholipase A2 (reduced arachidonic acid metabolites production) * Lymphopenia (as toxic to T cells) * Decreased T cells proliferation * Reduced immunoglobulins production (e.g. if given steroid drugs)

Answer 87

* Carbohydrate and lipid metabolism; diabetes, hyperlipidaemia * Reduced protein synthesis- poor wound healing * Osteoporosis * Glaucoma and cataracts * Psychiatric complications

Answer 88

* Autoimmune diseases- CTD (connective tissue disease), vasculitis, RA * Inflammatory diseases- Crohn’s, sarcoid, GCA/polymyalgia heumatic * Malignancies- Lymphoma * Allograft rejection

Answer 89

* Normally APC engages T cell which recognizes antigen=T cell stim= makes IL2 cytokine=allows spread of T cell activation (progression of immune response) Tacrolimus stops this * Cytokines= transcription of genes * Prolif stage= M-TOR signalling molecule allows T cells to proliferate - Sirolimus inhibits M-TOR * Drugs prevent different stages (targeted) * Anti IL-2 R mAbs blocks IL2 which also stops T cell-T cell activation * Azathioprine blocks T cell proliferation

Answer 90

* Antimetabolites; Azathioprine, Mycophenolate mofetil (MMF) * Calcineurin (serine/ threonine phosphatase) inhibitors; Ciclosporin A (CyA), Tacrolimus (FK506) * M-TOR inhibitors- Sirolimus * IL-2 receptor mABs- Basiliximab

Answer 91

Sirolimus (Rapamycin) • Macrolide antibiotic o Also binds to FKBP12 but different effects o Inhibits mammalian target of rapamycin (mTOR) • Binds mTOR- T cells can’t proliferate (stuck in G1-S phase) • Mode of action- inhibits response to IL-2 • T cell effects- cell cycle arrest at G1-S phase

Answer 92

• CyA- binds to intracellular protein cyclophilin • Tacrolimus (FK506)- binds to intracellular protein FKBP-12 • Cyclophilin & tacrolimus- immunosupressants by preventing T cell activation • Mode of action; o Prevents activation of NFAT o Factors which stimulate cytokines (i.e IL-2 and INFγ) gene transcription • T cell effects- reversible inhibition of T-cell activation, proliferation and clonal expansion

Answer 93

* Hypertension * Hirsutism (abnormal hair growth on woman’s face & body) * Nephrotoxicity * Hepatotoxicity * 2ndry lymphomas (due to long term immunosuppression) * Opportunistic infections * Neurotoxicity * Multiple drug interactions (induce P450)

Answer 94

* Transplantation- allograft rejection | * Autoimmune diseases

Answer 95

Inhibit nucleotide (purine) synthesis (interfere with DNA synthesis- so cell can’t multiply as can’t synthesis enough DNA, so will affect organs that have lots of cell proliferation) • AZA (azathioprine) o Guanine anti-metabolite o Rapidly converted into 6-mercaptopurine • MMF o Non-competitive inhibitor of IMPDH (inosine monophosphate dehydrogenase) o Prevents production of guanosine triphosphate • T and B cells effects o Impaired DNA production o Prevents early stages of activated cells proliferation

Answer 96

Folate antagonists

Answer 97

Cross-link DNA (so DNA synthesis will be impaired- cells won’t survive)

Answer 98

All can cause: o Bone marrow suppression & susceptibility to infections o Gastric upset (nausea) o Hepatitis * Cylophosphamide- cystatis (bladder inflamm) * MTX- pneumonitis

Answer 99

* AZA/MMF- autoimmune diseases (SLE, vasulitis, IBD), allograft rejection * MTX- RA, PsA, Polymyositis, vasculitis, GvHD in BMT * Cyclophosphamide- vasculitis (Wagner’s, CSS), SLE

Answer 100

``` Biologic DMARD’s (can target specific molecules) • Anti-cytokines (TNF, IL-6 and IL-1) • Anti-B cell therapies • Anti-T cell activation • Anti-adhesion molecules • Complement inhibitors ``` i.e : RA is treated with anti TNF tolicizumab, Anti-IL-17 mAb, Rituximab and Abatacept

Answer 101

Anti-Cytokines o First biologic drugs successfully used in therapy of RA (5 different agents now licensed) o Used in other inflammatory conditions (Crohn’s, psoriasis, ankylosing spondylitis) o Earlier use the drug- better the effect (before get further along in the pathogenesis) o Caution: increase risk of TB

Answer 102

Anti-Cytokines - Anti-IL-6 o Blocks IL-6 receptor o Used in therapy of RA and AOSD o May cause problems with control of serum lipids

Answer 103

Anti-Cytokines o 3 different agents available (anakinra, rilonacept and canakinumab) o Used in treatment of AOSD and autoinflammatory syndromes

Answer 104

• Chimeric mAb targets CD20 on B cell surface • First approved in ’97 for treatment of chemotherapy resistant DLCL • Only CD20 molecule in memory & transitional B cells so won’t affect all B cells- early B cells survive so immune system can reform • Many uses: o Lymphomas, leukaemias o Transplant rejection o Autoimmune disorders

Answer 105

``` • Bone marrow transplant (BMT) • Stem cell transplant (SCT) • Take progenitor cells out- kill all cells- put progenitor cell back • Uses o Immunodeficiencies (SCID) o Lymphomas and leukemias o Inherited metabolic disorders (osteopetrosis) o Autoimmune diseases ```

Answer 106

* Treatment of allergy usually steroids * Immune suppressants * Allergen specific immunotherapy- more targeted * Anti-IgE monoclonal therapy * Anti-IL-5 monoclonal treatment Allergen Specific Immunotherapy • Indications; o Allergic rhinoconjunctivitis not controlled on maximum medical therapy o Anaphylaxis to insect venom • Mechanisms; o Switching of immune response from Th2 (allergic) to Th1 (non-allergic) o Development of T reg cells & tolerance • Routes- SC or sublingual for aeroallergens • Side effects localized & systemic allergic reactions

Answer 107

* mAb Targets IgE * Used in Rx of asthma (where conventional therapy failed) * Also useful in Rx of chronic urticaria and angioedema * May cause severe systemic anaphylaxis

Answer 108

* mAb against IL-5 * Prevents eosinophil recruitment and activation * Limited effect on asthma * No clinical efficacy in hypereosinophilic syndrome

Answer 109

* Skin (barrier, sebum, normal flora) – e.g. burns * Mucous membranes (tears (keep eye surface clean), urine flow, phagocytes) * Lungs (goblet cells, muco-ciliary escalator (bacteria back up to surface). Cystic fibrosis- mucus stays in lungs) * Interferons, complement, lysozyme, acute phase proteins (not produced in reaction to a specific threat but just available) * Normal commensal flora in gut – antibiotic treatment alters flora e.g. can get C. difficile, Candida spp (CLOSTRIDIUM) infections. * (Extremes of age, pregnancy, malnutrition- more prone to infection)

Answer 110

• Can occur after taking antibiotics

Answer 111

At risk of; • (Staph aureus) • Pseudomonas infec • Group A strep infecs

Answer 112

* Neutrophils (NE) very important after initial breach of innate defences * Less – increasing infection

Answer 113

• Qualitative defects (neutrophils don’t work properly) (e.g. lose ability to kill or chemotaxis) or Chemotaxis – rare, congenital, e.g. inadequate signalling • Quantitative defects (not enough neutrophils- less present) Killing power - inherited, e.g. Chronic Granulomatous Disease. At risk of Staph. aureus infections

Answer 114

 Quantitative defects lack of neutrophil  Causes;cancer treatment, bone marrow malignancy, aplastic anaemia - drugs  “Neutropenic” – not enough neutrophils  Esp. imp. <0.5x10^9/L (neutrophil count where starts getting bad) and if prolonged (more risk of infec)  >50% proceed to infection. High mortality  Empirical therapy - Concept  >50% those with Pseudomonal infections will die in 24hrs if not treated  Need to give antibiotics that have Pseudomonas cover e.g. piperacillin tazobactam (broad spec & covers pseudomonas)

Answer 115

* Bacterial infections – e.g E. coli (in bowel- if ulcers get into blood), S. aureus (can get inside if break in skin)- often normal flora e.g. Coag neg staph (line infecs) * Fungal infections – Candida spp.(candidia in eye, or line infec) , Aspergillus spp. (spores inhaled- chest infecs) * Treatment – broad spectrum antibiotics. * e.g. Antipseudomonal penicillin +/- gentamicin (affects gram –ves), 2nd line treatment e.g. a carbapenem (meropenem) * fungi, viruses * Granulocyte stimulating factors (GCSF)- if neutropenic can induce GCSF to try to stim bone marrow making neutrophils again

Answer 116

* Congenital – rare – T helper dysfunction +/- hypogammaglobulinaemia * Acquired – drugs e.g. ciclosporin after transplantation (decreases graft versus host disease and rejection), steroids * Acquired – viruses e.g. HIV (affects T cells)

Answer 117

• May be intracellular • BACTERIAL – Listeria monocytogenes (associated with soft cheese), Mycobacteria • VIRAL – stem cell transplants - HSV (herpes simplex), CMV, VZV. Serological testing, prophylaxis and treatment with e.g. aciclovir and ganciclovir (antivirals) • FUNGAL – e.g. Pneumocystitis spp., Candida spp., Cryptococcus spp. (cryptococcal meningitis marker disease of HIV) (If someone has TB check for HIV too) cell deficiencies – Protozoan and Parasitic infections • Cryptosporidium parvum - oocysts shed by cattle/humans. Faecal oral route. Most patients recover after prolonged illness of up to 3 wks (if immunocomp. can go on longer). May take much longer in T-cell deficients. Symptomatic treatment only (in most cases) • Toxoplasma gondii- in cat faeces (preg ladies a bit T cell defieicent) • Strongyloides stercoralis- worm invades through skin, makes it’s way to gut (mostly asymptomatic but if immunosuppressed can get overgrowth of worms & hyperreaction, woems can go throughout body esp in lungs)

Answer 118

* Antibody problems!! * Congenital – e.g. X-linked agammaglobulinaemia (rare) * Acquired – multiple myeloma, burns * Usually ENCAPSULATED bacteria that cause problems e.g. S. pneumoniae * Parasitic that cause problems- e.g. Giardia lamblia * Treatment – Immunoglobulin (to replace antibodies- BUT every time give transfusion risk of giving infection)

Answer 119

* Hereditary, rare * Encapsulated bacteria most important organisms. Need complement to help kill organisms. * e.g. C5-8 then Neisseria meningitidis (gram –ve diplococci) is important in this particular complement deficiency * Frequent, serious S. pneumoniae infections as poor quality opsonisation

Answer 120

* Spleen - source of complement and antibody producing B-cells, removes opsonised bacteria from blood. * Causes - traumatic, surgical or functional e.g. sickle cell anaemia * Streptococcus pneumoniae, Haemophilus influenzae type B, N. meningitidis, malaria * High mortality, vaccination, prophylactic penicillin (if don’t have spleen to protect against the above microoganisms), education – seek help if unwell

Answer 121

* Are antibodies or other peptides- inhibit inflammatory cytokine signals e.g.tumour necrosis factor or TNF, inhibiting T-cell activation, or depleting B-cells. * E.g. used in severe rheumatoid arthritis * Risk of tuberculosis, herpes zoster, Legionella pneumophila, and Listeria monocytogenes

Answer 122

• Anti-rejection treatment suppresses cell mediated immunity to stop effects of cytotoxic T cells and natural killer cells. Degree of immunosuppression varies on how closely the donor and recipient are matched and organ involved. Diary of infections would get in course of organ transplantation • 1. The initial disease e.g. HBV • 2. Surgery and hospital admission e.g. S. aureus wound infection • 3. Organ receipt (organ they’re getting comes with risk) e.g. Toxoplasmosis, CMV • 4. Opportunistic infection during initial immunosuppression (initial 3/12, e.g. CMV, Aspergillus) • 5. Later on get opportunistic infection (after 3/12, e.g. Zoster, Listeria)- more T cell type infecs candid albicans can occur from line insertions give

Answer 123

* Immunofluorescent staining revealed blood group substances in cell membranes of all vascular endothelial cells & certain epithelial cells not just RBCs. * Normal individuals have naturally occurring anti-A or anti-B isoagglutinins (why you can have incompatibility) * Poor outcome of transplants performed between blood group incompatible individuals.

Answer 124

* Set of genes found in all vertebrate species * Important role in immune function, disease susceptibility and reproductive success. ‘ * Proteins encoded by the MHC are expressed at the cell surface and function to present ‘self’ and ‘nonself’ antigens for inspection by T cell antigen receptors. * 50,000 – 100,000 MHC molecules on the average mammalian cell (most common protein on cell surface) * MHC- mark your cell as yours so anything else as foreign * Highly polymorphic. * Role in histocompatibility, major influence on graft survival. The Human MHC • 6p21.3 • 3.6Mbp • Also known as ‘the HLA complex’ • Divided into three regions, class I, II and III. - class I region encodes HLA-A, B, C (‘classical’) antigens - class II region encodes HLA-DR, DQ, DP antigens - class III region encodes HSP70, TNF, C4A, C4B, C2, BF, CYP21 • Class I genes ~3-6kb • Class II genes ~4-11kb (larger) • Class I & II important in transplants

Answer 125

• Class I antigens: bind to Cytosolic pathogens (HLA-A, B, Cw) found on all nucleated cells- they present endogenous peptides form inside of cells. HLA CI A,B,C molecules composed of MHC encoded 45kd heavy chain non-covalently associated with non-polymorphic B2 microglobulin. CD8

Answer 126

• Class II antigens: bind intravesicular pathogens and extracellular pathogens and toxins (HLA-DR, DQ, DP) primarily expressed on B lymphocytes but expression can be induced on T lymphocytes and other cells- exterior env (take things inside cell to present) HLA CII DR, DQ, DP molecules composed of MHC encoded 31-34 kd associated a chain non-covalently associated with 26-29 kd B chain CD4

Answer 127

``` Mendelian inheritance (1:4 chance of being mismatched, 1:2 sharing, 1;4 complete match) • Inherit MHC en-bloc from each parental chromosome (HLA-A,B,Cw, DR, DQ,DP). Each individual inherits two antigens at a given locus. • Codominant expression. All of the inherited antigens are displayed on the cell surface (inherited block called HLA phenotype). ```

Answer 128

* Serological – cell based * Molecular * Extraction of DNA * Amplification * Detection of sequence polymorphisms (i.e. tissue type) * Hybridisation to probes * Sequencing

Answer 129

* Less rejection episodes * Better graft survival * National kidney waiting lists * Less sensitisation * Establish relationships

Answer 130

* Prevents hyperacute rejection * General – against many HLA types * Specific – against donor * Pretransplant crossmatch * Living or cadaveric * Avoids aborted transplant * Sensitising events * Previous transplant * Pregnancy * Blood transfusion

Answer 131

* Developed in 1970s * Detects complement fixing IgG /IgM HLA and non-HLAs * Advantages * >30yrs experience * Inexpensive * Disadvantages * Limited sensitivity * Subjective * Non-complement fixing abs * Viable reagent supply and quality control * Non HLA antibody interference

Answer 132

• Indirect recognition pathway; o Standard immunity o APC take up antigen, peptides presented to immune system= attack what’s causing insult • Direct recognition pathway; o ONLY happens in transplant o Donor APC cells migrate out of graft & interact with recipients white cells

Answer 133

* Immune response when exposed to foregin HLA, this could be through e.g. graft (e.g. a previous transplant), blood transfusions & female becomes sensitized during pregnancy (mum exposed to antigens in cells of baby) * Sensitization calc- if have pre-formed antibodies so sensitive to antigen * Cross match test; donor lymphocyte with HLA, interact donor cell & recip sreum (if it contains antibodies they will bind)- see if can get transplant

Answer 134

* Activates clotting cascade * Activate complement * Preformed antibodies * Xenograft rejection: Anti-Galα1-3Gal * ABO incompatible transplantation: ABO antibodies * HLA incompatible transplantation: Anti-HLA

Answer 135

``` cell dependent • Animal models • T cell immunosuppression • Directed against foreign HLA molecules • Effect of HLA mismatch • Typically 7- 10 days after transplant ```

Core Immunology Flashcards

(159 cards)