Flashcards in Immunology Deck (125):
Process of B cell development?
Haemopoetic stem cell -> Common lymphoid progenitor -> VDJ re-arrangement -> negative selection -> Naive B cells -> plasma cells -> Ig gene (2 heavy, 4 high chains)
Process of T cell development?
Haemopoetic stem cell -> Common lymphoid progenitor -> TCR gene re-arrangement via IL-7 -> positive and negative selection to MHC -> CD4 (helper cells) or CD8 (cytotoxic) T cells
Which T cells bind to MHC I?
CD8 cytotoxic cells
Which T cells bind to MHC II?
CD 4 helper cells
What is the role of AIRE (Autoimmune regulator)?
deletion of high affinity T cells and induction of thyme regulatory T cells (Treg cells) in the thymic medullary epithelial cells
What is Autoimmune polyendocrine syndrome Type 1 (APECED)? What are the 3 cardinal manifestations?
AR disorder due to mutated AIRE gene -> failure to express tissue specific antigens, failure to delete T cells, atuoreactive T cells released into the periphery -> Autoimmunity
Chronic mucocutaneous candiadiasis (antibodies to TH17)
AI Addison’s disease
What are the 2 types of T reg cells (CD4 positive cells)? Role of foxP3? Disorder of FoxP3?
There are 2 main subsets: natural/central and adaptive/peripheral
Natural develops in thymus , arise from action of AIRE
Adaptive develops in periphery and mostly in response to food, antigens and commensal organisms. Induce FoxP3. Require IL-2
Express transcription factor foxP3
Fox p3 is the master regulator of T reg cells and responsible for the development and function
Lack of Treg cells -> AI, allergy, lymphoproliferation
IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) is a rare disorder of defect in FoxP3
Presents in the 1st few months of life.
AI -> endocrinopathy, eneropathy (diarrhoea, FFT), haemolyic anaemia, ITP, AI neutropenia)
Atopic features e.g. eczema, food allergy, eosinophila
lymphadenopathy and splenomegaly
Whats is the role of CTLA4?
inhibitory signalling molecule expressed late on activated T cells to limit their expansion
What is the role of the dendritic cell?
Antigen presenting cells
Capture antigen, break into peptides, present on surface MHC molecules, express co-stimulatory molecules -> migrate to lymph nodes and spleen -> Initiate immune response by presenting foreign antigens to naive and memory T (Th and Tc) and B cells
What cells are involved in the innate immnune response? What is the onset of action? Receptors of the inmate immune system and roles?
Within 12 hours
Phagocytes, NK cells, dendritic cells, complement
Structures on microbes recognised by PAMPS (pathogen associated molecular patterns)
Structures in injured tissues and dead cells recognised by DAMPS (danger associated molecular patterns)
PAMP receptors are toll-like receptor, mannose binding lectin receptors, NOD like receptors, RIG receptors
Toll like receptor - binds bacterial lipopolysaccharides -> induce cytokines, co-stim molecules. Responsible for gram-ve shock sepsis
MBL receptos - acts as opsonin and facilitates uptake by macrophages
NOD like receptors - cytosolic sensors, complex is inflammasome. Sense pathogens and cell danger signals DAMPs -> activate caspases (1,4 or 5) and these activate and release IL-1B and IL 18 -> imflammation
RIG - 1 receptors (RLR) - receptors for RNA viruses, located in cytoplasm, respond by releasing type 1 IFNs and inflammatory cytokines
What is the pathophys of GOUT?
An inflammasome mediated disease
caspase 1 activated -> release IL-B -> acute inflammation
Anakinra acts on IL1
MOA of colchicine?
Inhibits microtubule formation and uncouples urate crystals from inflammasome reaction
What are plasmacytoid dendritic cell (pDC)?
Direct lineage to dendritic cells
Respond to viral infection -> express TLR in endosomes, express RLR in cytoplasm
Release lots of IFN -> induce rapid viral state and alter cellular processes
What is the difference between antigen recognition of B vs T cells ?
B cells recognise intact antigen
T cells require Ag to be processed and expressed with MHC. Class I for CD8, Class II for CD4
What is the role of the MHC?
Presentation of peptides to T cells
What is HLA? Location? No. of classes? Role of each?
Human leucocyte antigens, human equivalent of MHC.
On chromosome 6p.
Divided into Class I, II and III
HLA Class I - HLA -A, B, C.
consist of single 3 domain chain and B2 microglobulin. Expressed by all cells except RBCs and some neuronal cells. Presents peptide derived from degraded intracellular proteins (viruses + bacteria) to CD8 T cells. B2 micro globulin is the binding groove.
Essential role in eliminating virally infected cells
HLA Class II- HLA DR-DP, DQ
expressed only by specialised APCs and unregulated by inflammatory stimuli
Role in activation of CD4 cells -> Presents peptide to CD4+ T cells
Consist of two 2-domain chains - alpha and beta
a1 and 2 domains are the binding grooves
Role in uptake of extracellular proteins into compartments of APC, Binds peptides derived from degraded extracellular proteins (all types of foreign invaders)
What 3 factors are required for T cell activation?
MHC + peptide + Co-stimulation
Co- stimulation is mediated by B7.1 CD80 and B7.2 CD 86 (essential con-simulators on APC. Interact with CD28 (activation) and CTLA-4 (delayed de-activation).
MOA of Abatacept? AE?
Anti-CTLA-4. Blocks and depletes T cells with suppressive potential ->stimulates the immune response
AE: AI disease (endocrine and IBD)
Role of IL-2? Use?
Critical for the generation of T reg cells -> drives T cells division
Used in RCC
MOA of calcineurin inhibitors (Cyclosporine, tacrolimus)?
Inhibit IL-2 induction to inhibit proliferation of lymphocytes
What do TH1 helper cells differentiate in response to? What do they secrete? Action?
TH-1 cells secrete IFN-y, TNF and lymphotoxin to activate macrophages, induce specific Ig isotopes on B cells, activate NK cells, defence against intracellular pathogens.
What do TH2 helper cells differentiate in response to? What do they secrete?
Role in inducing atopic response -> IgE production by B-cells (IL-4, 13), eosinophils (IL-5)
Defence against helminths
What do TH17 cells differentiate in response to? What do they secrete? Action?
IL-6 or IL-21 and TGF-B
Secrete IL-17 -> stimulate cells to release cytokines and chemokines that attract neutrophils, stimulate release of defences and the AMPs
Defence against candida, staph
Which T cells are involved in atopy?
Dominated by TH2 response
IL-4 acts on Naive T cells to create more TH2 cells and B cells to promote IGE switching
IL-13 acts on B cells to promote IgE switching
IL-5 attracts eosinophils
Describe the cascade of immediate hypersensitivity reaction?
Allergens -> antigen presentation -> IgE production -> mast cell activation -> mediator release (histamines, leukotrienes, cytokines)
What is the immune response to a pathogen?
Antigen exposure -> 1st antibody made is IgM (low affinity, 10 effective binding sites), later IgG (higher affinity)
Subsequent antigen exposure -> same IgM response and faster better IgG response
Describe isotype switching of B cell antibodies?
Activated B cells can change surface Ig from IgM/D to IgG,A and .
Re-arranged VDJ is coupled with a downstream C region gene
What is the role of an antibody?
Activate B cells when surface Ig crosslinked by antigen
Neutralisation of toxins (tetanus), viruses, bacteria
Activate complement -> cytotoxicity
Opsonisation -> coat target with IgG and complement to enhance phagocytosis. Occurs via Fc and C receptors on phagocyte surface
Ab-dependent cell mediated cytotoxicity (ADCC)
Role of Memory B cells?
Surface Ig expressing (usually isotope switched)
Long lived B cells
Able to respond to secondary challenge faster
What are the antibody forming cells?
Lymphoblasts, plasmablasts, plasma cells
What are the 3 complement pathways?
All meet at common pathway C3-C3b
Role of C1?
C1-> activated to C1q binds to Fc portion of Ab-> binds directly to bacteria, binds to CRP, binds to Ab (igM->IgG)
Role of C4?
C1 cleaves C4 into C4a and C4b
C4C2b activates C3->C3b (classical/lectin C3 convertase)
Role of C3b?
Antigen coated with Ab and complement -> efficient uptake by APC Fc receptors and C’ receptors
Role of Lectin pathway?
3rd part of C activation.
Activated by manose binding lectin (MBL) and Ficollins 1-3.
Cleaves C4 and C2 on activation
Role of MAC?
Cleavage of C5 to C5a and C5b
C5b binds C6 and C7 - confers lipophilicity i.e. can insert into lipid bilayer
C8 binds - confers some lytic activity
Many C9 bind -> membrane damage and lysis of target cells. Pores formed.
Activated macrophages release pro-inflammatory cytokines to act on hepatocytes to release acute phase reactants. What are they?
Alpha 1 anti-trypsin
How are NK cells developed? Role?
Develop from common lymphoid precursor in response to IL-15
Kill virally infected cells (antibody dependent cell mediated cytotoxicity, ADCC), tumour cells, releasing cytokines (IFN-y) to activate adaptive immune system, major cell of regnant uterus
ADCC- IgG binds to viral Ag expressed on surface of infected cell, NK becomes activated and kills via perforin granzyme or Fas pathway
ADCC - IgE. eosinophils when activated express the high affinity receptor for IgE -> targets helminths, binds to eosinophils via Fc and induces degranulation and release of eosinophil toxic proteins
What are the 2 NK cell receptors?
Killer activating receptors -> attack -> perforin and granzymes
Killer inhibitory receptors -> recognises MHC normal cell -> no attack
Why are RBC not attacked by immune cells?
No activating receptor
Lack of antibodies result in which type of infections?
Recurrent sinopulmonary and gut infection
Infections by polysaccharide encapsulated pyogenic organisms (Strep pneumoniae, Strep pyogenes, H. influenza typeB, Branhamella catarrhalis), staph aureus, giardia, campylobacter.
Lack of T cells result in which infections?
infections with intracellular organism (as per AIDs) e.g. fungi (mucosal candida), Viruses (CMV, HSV, VZV, Protozoa e.g. pneumocyctis, listeria), mycobacterial infecion (MAC, M. Tb)
Lack of neutrophils result in which infections?
Invasive aspergillus, systemic candidiasis
Gram -ve bacteria - E.coli, P. mirabilis, Serratia, Pseudomonas aeruginosa and cepacia
Lack of complement C1, C4, C2, C3 results in?
C1q, C1r, C1s - SLE, pyogenic infections
C2 - SLE, vasculitis, GN
C4 - SLE, glomerulonephritis
C3 - GN, immune complex disease
Lack of complement components in alternative pathway:
Properdin, Factor D
Factor I, H, MCP, C3 and Facor B results in which infections?
Properdin, Factor D- Neisserial infection, other pyogenic infections
Factor I, H, MCP, C3 and Facor B - Atypical HUS, gain of function mutation
Lack of terminal components C5,6,7,8,9 results in which infections?
Disseminated Neisserial infections
What is the most common primary immune deficiency in adults? Incidence? Clinical features? Ix? Tx?
- 1 in 10 000
- M:F 1:1
- 10% familial - often associated with IgA def
- Occurs at any age, 2 peaks 2-5y and 18-25 y
Recurrent sinopulmonary infections (sinusitis, bronchitis, tonsiliits, pneumonia, otitis media)
Gut infections - chronic or recurrent infective diarrhoea (giardia)
Malabsorption, diarrhoea - sprue like syndrome with nodular lymphoid hyperplasia of the S1 does not improve with gluten free diet
T cells infections uncommon but increased e.g. mycobac, fungal, PCP
Autoimmunity in 20% - immune cytopenias (ITP, AIHA), thyroid, pernicious anameia, polymyosists, vitligo
Cancer- lyphoma (up to 400 x risk of NHL), stomach
Lymphoproliferation - lymphadenopathy, splenomegaly, granulomatous disease,
Bronchiectasis and resp failure
Chronic infection - amyloidosis
IgG low (one or both IgA/IgM also decreased)
B cell count normal
EPG - hypogamma
Impaired vaccination response
IVIG 0.4g/kg monthly SC infusion
Antibiotics - start early, treat for longer, identify organism, prophylactic
Avoid live vaccines
What are the secondary causes of hypogamma?
Drugs - carbamazepine, sulfasalazine -> can mimic CVID
GI protein loss
What are the genetic causes of CVID?
Atypical forms of other primary antibody deficiencies e.g. X-linked agam, X -linked lymphoproliferative
CVID phenotypes - heaps!
What is the defect in X-linked agammaglobulinaemia? Epi? Clinical presentation? Ix? Tx?
No B cells!
No lymphoid tissues
Absence/mutation of Bruton’s TYR kinase (Btk), a signalling molecule essential for B cell development
Early onset 6 months
Family Hx in 50%
B cell type resp infection and GIT, malbasorption, polyarthropathy
EPG - hypogamma
Ig levels undetectable
B cell count 0
B cell precursors are present in BM
Btk expression by flow cyt
Genetic analysis of BtK gene
IgA def: What? Epid? Clinical presentation? Associated disease? Ix? Tx?
Sporadic, sometimes familial, in families with CVID
Drug induced - phenytoin, penicillamine
Intrauterine infection - Toxo, rubella, CMV, Herpes (TORCH)
Many asymptomatic as can recruit IgM into the secretions
Mucosal infections like CVID, XLA - sinopulmonary and giardiasis
Cow’s milk allergy
GIT disease - nodular lymphoid hyperplasia, IBD, Coeliac disease
Anaphylaxis - transfusion of IgA containing blood products, due to anti IgA abs
AI disorders - RA, SLE, JRA, DMS, Sgrogren’s, ITP, perciicous anaemia, thyroiditis, Addison’s, AI -CAH
EPG - normal
Ig - absent IgA
B cell count normal
Does not require Tx
Abx therapy for acute episodes
No IVIG as mucosal, not systemic defect
Pts should be transfused with IgA deficient donors or triple washed cells
IgG subclass def: Epi, Clinical, Ix, Tx?
Usually IgG2 or IgG3 are low. If IgG1 low usually CVID
Recurrent sino-pulmonary infections
IgG levels may be normal or borderline low IgG
IgG subclasses def in >=1
Bcell count normal
Consider IVIG if high freq of recurrent bacterial infections
HyperIgM syndrome type 1: What? Epid? Clinical? Ix? Tx? Cx?
Absent CD40-CD40L signal -> failure of B cell isotype switching and memory B cell generation. Impairment of APC: T cell interaction.
Due to def or mutated T cell CD40L.
Age 1-2 y
Recurrent bacterial infections, resp and especially PJP
Acute and chronic diarrhoea e.g. crypto, oral ulcers, proctitis
Decreased IgA, IgG, IgE
Normal of increased IgM
Normal B cells that express IgM, IgG
Impaired antibody response to T cell dependent antigens
Dx with flow cytometry to detect CD40L
increased incidence of malignant and AI disease
What is Idiopathic CD4 T cell lymphopenia? Causes? Clinical? Ix? Tx?
Low CD4 count, HIV negative
T cell type infections e.g. oesophageal candidiasis, MAC infection, diseeminated VZV, crytpococcal pneumonia/meningitis
>= 1 clinical condition indicating severe immunosuppresion
CD count below 300/uL or 20% of lymphocytes
No secondary causes and repeatedly HIV seronegative. BEWRE of T cell lymphomas
Consider prophylaxis of opportunistic infections
What is chronic mucocutaneous candidiasis? Epi? Clinical? Ix?
Chronic or recurrent candida infections due to a lack of TH17 cells
Types: Genetics, thymoma associated
Onset in childhood
Affects nails, skins, mucosae, oesophageal and pulmonary
lack of Th17 cells
What is SCID? Epid? Clinical?
Lack of component essential for T cell function, lacking Gamma-common chain
FTT, chronic diarrhoea
Recurrent opportunistic infections e.g. fungal, virus, protozoal esp PJP
What is chronic granulomatous disease? Epid? Clinical? Ix? Tx?
Rare, X- linked.
Due ro defects inphagocyte NADPH oxidase - Molecular defect of 1 of 4 subunits of NADPH oxidase responsible for resp burst in neutrophils. Necessary for killing cells.
Age typically paediatric, incomplete defects sometimes in adulthood
Recurrent infections with co-agulase negative bacteria and fungi e.g. staph aureus, aspergillus
Abscesses - skin, lungs
Lungs - recurrent bronchopneumonia
Other tissues - lymphadenitis, Crohn’s like syndrome, osteomyelitis
NBT test - test ability of granulocytes to generate reactive O2 species for microbial action
Flow cytom for dihydrohordamine reduction
Chronic ABx - Bactrim and itraconzaole (fungul)
What is the rationale for using combinations in HIV protease inhibitors? MOA Ritonavir
Improved pharmacokinetic profile
Ritonavir component inhibits the CYP3A metabolism of lopinavir -> increased plasma levels of lopinavir
MOA of lopinavir (PI)?
Binds to the site of HIV-1 protease activity nd inhibits the cleavage of viral Gag-Pol polyprotein precursors into individual functional proteins required for infectious HIV -> formation of immature noninfectious viral particles.
Cytokines, their source and their clinical relevance? IL- 1, 2, 4, 5, 6, 8, 11 to 12, TNF, interferon B and Y
IL 1 - macrophages -activate T cells and macrophages
IL 2- - TH1 cells - activate lymphocytes, NK cells and macrophages
IL 4 - TH2 cells, mast cells, basophils and eoasinophils - activate lymphocytes, monocytes and IgE class switching
IL-5 - TH2 cells, mast cells, eosinophils - differentiation of eosinophils
IL 6 - TH2 cells and macrophages - activate lymphs, differentiation of B cells, stimulate production of acute phase proteins
IL -8 - T cells and macrophages - chemotaxis of neutrophils, basophils and T cells
IL-11 - bone marrow stream cells - stimulation of the production of acute phase proteins
IL- 12 - macrophage and B cells - stimulate production of interferon by TH1 and NK induction of TH1
TNF - macrophages, NK cells, T cells, B cells and mast cells - promotion of inflammation
IFN B -virally infected cells - induction of resistance of cells to viral infection
IFN Y - TH1 and NK cells - activation of macrophages, inhibition of type 2 (TH2) helper cells
What is the most common consequence of the Panton-Valentine Leucodin (PVL) toxin secreted by S. aureus?
Necrotising soft tissue and mucosal destruction that cause pyogenic cellulitus and necrotising pneumonia
What hypersensitivity reactions are associated with Type 1,2,3, 4 and 5?
T1- allergy - IgE- oedema e.g. astham, anaphylaxis, atopy
T2 - antibody dependent hypersensitivity - IgM or IgG, complement and MAC - auto-abs against RBCs-> haemolysis e.g. AIHA, thrombocytopenia, good pastures, graves disease, MG
T3- Immune complex reactions - IgG, complement, neutrophils - SLE, GM, RA, Mantoux test
T4 - delayed type hypersensitivty, cell mediated immune memory response - T cells - contact dermatitis, mantoux test, chronic transplant
T5 - AI disease receptor mediated - IgM of IgG - grave’s disease, MG
MOA of Treg drugs? Examples of Treg drugs?
Increasing reg T cells that decrease Th cells to reduce inflammatory process
Leucocytoclastic/Hypersensitivity vascultitis: What? Epid? Causes? Clinical? Ix? Dx? Tx? Cx?
A leukocytoclastic vasculitis mainly involving skin (definition according to meeting 3/5 defining criteria) aka drug induced, serum sickness, allergic vasculitis
Drug reaction - most common is sulphonamides, penicillin, cephalosporins, allopurinol, phenytoin
Secondary to HCV, HBV, HIV, chronic bacteraemia
Skin - palpable purpura
Fever, urticarial, arthralgias, lyphadenopaty
Sx begin 7-10 days after antigen exposure
Should clear once Ag clear
Skin biopsy - inflammation of blood vessels. PMN cell predominant.
1. Age > 16 years
2. Temporal relationship with drug (not necessarily a new cessation)
- Drug acts as a hapten (molecule that when bound to a protein, stimulates the production of Ab)
3. Palpable purpure
4. Macular papular rash
5. Perivascular neutrophils on biopsy
Stop offending drug
If severe cutaneous disease- colchicine, antihistamines, dapsone
Immunosuppresion if fulminant or progressive
Cyroglobulinaemia: What? Types? Ix?
Serum proteins that precipitate in the cold and dissolve upon rewarming. Contains a mixture of Ig and complement components.
Monoclonal - type 1
- associated with monoclonal gammopathies. 20%. IgG/IgM > IgA/free light chains
- hyperviscosity/ischaemia related to Raynoauds, Livedo reticualris, purpura, neurological Sx. Affects skin, Kidney, BM
- associated with myeloma, waldonstroms. Usually haematological malignancies
Polyclonal- Type 2
- mixture of polyclonal Ig + monoclonal Ig (monoclonal IgM RF directed against IgG)
- associated with persistent viral infections - Hep C, HIV, HBV, EBV
Polyclonal - Type 3
- polyclonal Ig (both IgG and RF IgM is polyclonal)
- associated with CTD, HCV
Symptoms of type 2 and 3- Meltzer’s triad - palpable purpura, arthralgia, myalgia
Complement decreased, esp C4
Acute phase reactants increase
HCV, HBV, HIV
Renal Bx if indicated
What conditions are associated with c - ANCA vs p-ANCA?
c-ANCA = GPA (Wegeners), although can be p-ANCA positive
p-ANCA = EPA (Churg Strauss)
Eosinophilic granulomatosis with polyangiitis (EPA aka Churg Strauss): What? Epi? Causes? Clinical? Dx? Ix? Tx? Cx?
Allergic granulomatosis and angiitis. Small and medium sized array vasculitis
Mostly Dx in Asthma pts
1- prodromal - atopic disease, allergic rhinitis, asthma (95%) in 2nd-3rd decades of life
2- eosinophilic phase - serum eosinophila, eosinophilia infilctration of multiple organs esp lung and GIT
3- vasculitic phase - life threatening systemic vasculitis with vascular and extravascular granulamatosis in 3rd-4th decades of life. Constitutional symptoms.
- mononeuropathy or polyneuropathy
- pul opacities
- paranasal sinus abnormalities
- +ve vessel Bx
Corticosteroids for remission induction
If five factor score = 1 - plus cyclophosphamide or rituximab
Life threatening - plasma exchange
50% die from cardiac death
cyclophosphamide haemmorhagic cystitis and infertility
What is the best method for testing for a penicillin allergy?
Skin prick and intradermal testing for penicillin - high NPV
Testing for IgE levels in serum not useful as penicillin allergy can wax and wane over time
Why is HLA B5701 genotype screened prior to starting patients on abacavir in HIV clinics?
Assess risk of hypersensitivity reactions
What is abacavir? AE
Nucleoside analogue reverse transciptase inhibitor (NRTI)
What is tenofavir? AE
analogue of 5- monophosphate that interferes with DNA replication. NRTI.
80% renal excretion and can cause acquired renal tubular dysfunction (Fanoconis)
Efarivenz MOA? AE?
NNRTIs reversibly inhibit HIV‑1 reverse transcriptase, reducing viral DNA synthesis.
CNS (dizziness, anxiety etc), derm (rash), increased chol/HDL/TG, GI symptoms are the most common SE
Adefovir MOA? Indication? AE?
a nucleotide analogue of deoxyadenosine monophosphate, which acts as an alternative substrate for viral DNA polymerase resulting in DNA chain termination and prevention of viral DNA synthesis.
Indicated in Hep B Tx
AE: CNS (headache), MSK (weakness), hepatic (LFTs) and renal (hematuria) most common SE. Lactic acidosis is infrequently reported
IRIS: What? Pathogens associated? Clinical? Ix? Dx? Tx?
describes a collection of inflammatory disorders associated with paradoxical worsening of preexisting infectious processes following the initiation of HAART in HIV infected individuals
Depends on underlying infection e.g. TB
Sx within a week - few months of starting HAART
HAART may decrease HIV viral burden up to 90% within 1-2 weeks of starting Tx.
Nil if IRIS highly likely
1) presence of AIDS with low pretreatment CD4 (~ 200)
2) positive virologic and immunological response to ART
3) absence of evidence of drug resistant infection/ bacterial superinfection/ drug allergy/ non compliance etc
4) clinical manifestations consistent with an inflammatory condition
5) temporal association between HAART initiation and onset of illness clinical features
Treat underlying pathogen
NSAIDs/Steroids may decrease inflammatory response
HIV enters CD4 cells via which protein?
recognizes CD4 and 7-transmembrane receptor(CCR5 and CXCR4)
R5 Strain: uses CCR5 for CD4 cell entry (less aggressive)
X4 strain: uses CXCR4 for CD4 cell entry (more aggressive)
Which amyloid disease is associated with dialysis?
dialysis related B2 micro globulin, presents as arthropathy
What is serum amyloid A (secondary amyloid) associated with?
Chronic infections or inflammatory conditions.
What is the most common type of Amyloid?
Amyloid light chain (AL)
Due to clonal population of B cells
Deposition of fibrinogen a chain (AFib) is a familial condition associated with which type of amyloid?
Which type of amyloid is transthyretin associated with?
Familial form, AD
manifest in mid life with neuropathy and cardiomyopathy
Hypersensitivity reactions Type I-IV?
Type 1 - IgE mediated
Type II - Antibody mediated
Type III - Antigen-Antibody immune complexes
Type IV - Delayed type hypersensitivity reaction with macrophages and eosinophils playing a key role
Anaphylactoid reactions occur as a result of systemic compliment activation and is predominantly due to release of?
C5a generates anaphylactoids
What is Familial Mediterranean Fever? Presentation? Tx
Most common genetic auto inflammatory syndrome
Mutations in MEFV gene which codes for protein perinea.
Pyrin is a protein present in the inflammasome- > inappropriate activation of the inflammasome leading to the release of pro-infllam cytosine IL-1B
Short episodes lasting
Hereditary angioedema. What? Presentation? Dx? Tx?
AD disorder caused by a DEFICIENCY or DYSFUNCTION in C1 inhibitor with seondary decreased C4 because on ongoing consumption.
Angiooedema due to excess bradykinin.
Type 1 (85%) = decreased INH enzyme
Type 2 (15%) = non functioning C1-INH enzyme
Screen by checking C4 levels
Dx by decreased C1-INH functional assay. If C1 levels low than Type I, if normal than Type 2.
FFP protective if given before minor Sx
Androgens increase C1-INH levels and decrease swelling episodes
C1-INH for IV use and kalikrien inhibitor (Ecallantide) for SC injection for acute attacks
Bradykinin receptor antagonist (Icatibant)
Ecallantide (kallikrein inhibitor) results in decreased bradykinin that is activated by protease kallikrein.
What is the most common malignancy associated with CVID?
Gastric cancer also common - role for chronic H. pylori infection, pernicious anaemia, altered p53 function
What is the difference between CVID and XLA?
deficiency of IgG, A and/or IgM
Prone to infections with encapsulated organisms and giardiasis
Ig assay shows low IgG, IgA, and/or IgM
Pts have mature B cells present
Tx: replace Ig with exogenous IVIg or SC Ig
Ig assay shows very low IgG, no IgA, IgM, IgE or IgD.
No B cells present
Susceptible to enteroviral infections and Giardia
MOA of CRP?
binds to phosphocoline thereby permitting recognition both of foreign pathogens that display moiety and phospholipid constituents of damaged cells.
Primary function is anti-inflammatory.
Rapid response indicates it is a component of the innate immune system.
What test confirms CVID?
Sig low IgG
Low IgA and or IgM
What is IgG4 disease? Tx?
Rare TH2 cell immune mediated inflammatory disorder characterised by elevated levels of IgG4 and infiltration if I gG4 bearing plasma cells into involved organs resulting in tumour like swelling.
Manifestas as AI pancreatitis, salivary gland and lacrimal gland, sclerosing cholangitis
What is the pathogenesis of SJS?
T cell mediated cytotoxic reaction agains kertonilytes leading to massive apoptosis.
Drugs can stimulate the immune system by binding directly to the MHC I and T cell receptor ->clonal expansion of drug specific cytotoxic T cells that kill keratinocytes directly and indirectly through the recruitment of other cells that release soluble death mediators such as granulising.
What type of immunologic reactions are caused by medications?
Type 1- immediate in onset and mediated by IgE and mast cells/basophils
Type IV - delayed in onset and T cell mediated
Delayed onset is after 1 hour, however most occur 6 hrs/days after Tx
What is the GOLD standard for Dx of IgE mediated food allergy?
Skin prick is highly sensitive. Only moderately specific.
Highly effective for excluding IgE mediated allergy in patients with a low pretest probability.
What are the types of Hereditary angioedemas? 3 types
- marked reduction in C1-INH level
dysfunctional protein, C1 INH normal
Type III - exclusively in women, oestogen related
What are the types of Acquired angio-oedema? 2 types
- consumption of C1-INH
- due to auto-antibody to C1-INH (C1-INH level normal)
What is the most sensitive test of hereditary/acquired angio-oedema?
How do you differentiate between the two?
Low C4, C3 normal
Check CI- INH, if low then Hereditary
Also check C1q levels
- low in acquired
- Normal in hereditary
What is Adult Onset Still's disease?
Rare systemic inflammatory disease
Characterised triad of by fevers OD or BD, joint pain and distinctive salmon pink, evanescent (comes and goes), non pruritic, macular papular rash.
High Ferritin but not Dx
CK can be elevated
What is Omalizumab?
humanosed monoclonal ab that binds to free IgE and prevents mast cells
In what conditions is tryptase elevated?
Enzyme released by mast cells
T-cell receptors are made of..?
What do T cells rely on to transduce signals?
T cell receptors are made of alpha and beta chain.
5-10% of TCR are composed of gamma and delta chains.
Each chain consist of variable and constant extracellular domain, a hydrophobic transmembrane region and a short cytoplasmic region.
T cells rely on co-receptors to transduce signals.
Require CD3 and ⑀ chains, they submit some of the signals that lead to T cell activation.
TCR recognise and bind to peptide MHC complex with relatively low affinity. T/F
Requires additional cell surface adhesion molecules to stabilise binding to APCs.
What differentiates between antigen-dependent and antigen independent B cell development?
How do B cells develop?
Progenitor B cell proliferation
VDJ gene re-arrangement
Produces Ig variable regions that specifically bind antigen
How are B cells activated?
Antigen binding and co-stimulation
Causes differentiation into memory B cells or antibody secreting plasma cells
Occurs in germinal centres of secondary lymphoid tissues - somatic hypermutation and class switch recombination.
Describe B cell differentiation
Ig light chain-like molecule covalently associated with Ig heavy chain molecule to male the pre B cell receptor.
u(mu) heavy chain expressed by IgM
What constitutes the B cell receptor?
CD79a (IgA). CD79b and membrane bound Ig on B cells together constitute the B cell antigen receptor.
CD79a appears at the preB cell stage and persist until the plasma cell stage Ig gene re-arrangement
B cell differentiation. What occurs before and after antigen exposure?
VDJ re-arrangement occurs before the antigen exposure and isotype switching occurs after antigen exposure.
Which Ig crosses the placenta?
IgG is the only Ig to cross the placenta.
What Ig is provided in breast milk?
Will provide enteric protection but not absorbed
Active immunisation vs. passive immunisation. What is the difference?
- uses exposure to non-pathogenic microbes to stimulate a protective adaptive immune response. Leads to the production of neutralising antibodies against microbila antigens.
- administration of Ig to provide short term protection
Why should live vaccines not be given to pregnant pts?
Foetus is vulnerbale due to lack of T cell mediated immunity
In order to achieve herd immunity, what is the minimum percentage of children required to undergo vaccination?
Herd community cannot be achieved.
Can only be achieved in infections that depend on human transmission only e.g. diptheria.
CVID? What, prevalence, presentation, Tx?
Impaired B cell differentiation resulting in low levels og IgG with low levels of IgA and/or IgM.
Dx between 20-45 y
Genetic mutation in
Complication of Raynaud's?
transition to defined secondary rheumatic disease within 2-3 years of Raynaud's presentation.
Positive ANA is associated with eventual development of AI rheumatic disorder.
Positive anticentromere antibody -> specific for development of CREST (limited systemic sclerosis)
Positive Scl70 antibdoy specific for development of scleroderma
Combination of autoabs and nailfold capilalry greatly increases prognostic yield
Mx of a pt with anaphylaxis not responding to repeated doses of IM adrenaline and IVF and antihistamines?
IV glucagon 2 mg.
Glucagon has inotropic and chronotropic effects that are independent of catecholamines.
Pt may not be responding due to BB.
When is antibiotic desensitisation indicated?
Pts with immediate hypersensitivity and no other alternative drug options. e.g. laryngeal oedema.
Graduated doses of drug given to induce temporary tolerance. When the Tx is discontinued, sensitivity to the medication returns.
Avoid in pts with serious reactions e.g. blistering skin reactions
Not indicated in nephritis, hepatitis.
When is HIV Tx indicated in pregnant women?
ART Tx should be commenced in all pregnant women with the aim of reducing maternal HIV load and decreasing the risk of transmission.
HIV genotype should be performed to inform the choice of Tx.
Tx should commence immediately if there is a clinical indication, otherwise commence in the 1st trimester.
Indications for HIV Tx?
HIV Tx. What is virological failure and immunological failure.
- inability to achieve or maintain suppression of viral replication
- inability to achieve a CD4 count of > 200 depite virological suppression.
- increasing age
- low baseline CD4 count
- co-infection with hep C
- drug interactions
Causes of HIV Tx failure
Poor adherence is No 1
Drug resisitance - poor adherence or new infection
Drug AE or toxicty
Pharmokinetics (drug interactions)
Other co-morbidities e.g. depression
What is a plasma cell?
Effector B cells that secrete antibodies/Ig
Develop in response to antigenic stimulation in peripheral lymphoid organs
What do Helper T cells recognise on APC?
processed antigen and HLA Class II
Measles, Mumps, Rubella
Large granular lymphocytes?
Natural killer cells
derived from common lymphoid precurser in response to IL-15
Cell population responsible for pathogenesis of sarcoid?