Immunology Flashcards
What is a Type I hypersensitivity reaction?
Mechanism: IgE mediated
Clinical Symptoms: urticaria, angioedema, anaphylaxis, anaphylactic shock, bronchial asthma, rhinitis, eczema
What is a Type II hypersensitivity reaction?
Mechanism: IgG-mediated cytotoxic hypersensitivity (i.e. antibody mediated)
Clinical symptoms: Autoimmune haemolytic anaemia, thrombocytopenia, blood transfusion reactions; bullous pemphigoid
What is a Type III hypersensitivity reaction?
Mechanism: immune complex mediated hypersensitivity; Ag-Ab complexes deposit and induce complement / inflammatory/ neutrophil response
Clinical symptoms: Vasculitis, GN, Organ specific reactions; SLE
What is a Type IV hypersensitivity reaction?
Mechanism: T cell-mediated hypersensitivity
Th1 cells activate macrophages or Tc cells
Clinical symptoms: SJS; TEN; DRESS; fixed drug eruption; contact dermatitis; delayed urticaria; MS; Scabies; GVHD; TB skin reaction
What is the function of IL-1?
Central regulator of the inflammatory response
Proliferation of activated T cells, B cells
Produced by macrophages, dendritic cells
What is the function of IL-2?
Produced by T cells
Growth of activated T and B cells
Activation of NK cells
What is the function of IL-3?
Produced by T cells, macrophages
Mast cell growth
Growth and differentiation of haematopoetic precursors
What is the function of IL-4?
Produced by T and B cells, macrophages, mast cells and basophils
Activation of B cells to promote IgE switching
Differentiation of Th2 cells
What is the role of IL-5?
Produced by Th2 subset, mast cells
IgM, IgA production
Driver ofWCC differentiation to eosinophilic pathway
Activated B cell proliferation
What is the function of IL-6?
Produced by T cells, macrophages, monocytes
Production of acute phase proteins
Growth and differentiation of haemopoetic cells
FEVER
What is the role of IL-8?
Produced by T cells, monocytes and neutrophils
Activation of Neutrophils
What is the function of IL-10?
Produced by T and B cells, macrophages
Suppression of macrophage functions & Th1 cells
Activation of B cells
What is the function of IL-17?
Produced by CD4 T cells, ILC3, NK cells
Promotes inflammation by increasing production of pro inflammatory cytokines (IL-1, IL-6, TNF alpha, G-CSF, GM-CSF) by epithelial, endothelial & fibroblast cells
IL-17 Deficiency = Job Syndrome
What is the function of TNF alpha?
Produced by macrophages, lymphocytes, neutrophils, eosinophils, NK cells
Activates macrophages, granulocytes, cytotoxic cells and endothelium
Enhanced HLA class I expression
Stimulation of acute phase response
Anti-Tumor effects
What is the function of TNF beta?
Produced by CD4 T cells Acute phase proteins Anti viral / anti parasite activity Activation of phagocytes Induce pro inflammatory cytokines
General function of Tumor Necrosis Factor?
Transmembrane protein - can be cleaved and released to act as a cytokine
Principle mediator of response to gram negative bacteria
What is the function of IFN-alpha?
Produced by leukocytes
Antiviral; up-regulates MHC Class I
What is the role of IFN-gamma?
Antiviral macrophage activation
Enhance HLA class I and class II expression
Characterises Th1 cells
Suppression of Th2 cells
Antagonises IL-4 effect
Stimulation of macrophages and endothelium
Aberrant IFN-gamma expression is associated with a number of auto inflammatory and auto immune conditions e.g. MS
What is BAFF?
B-cell-activating factor Member of of the TNF family Cytokine that promotes B cell maturation, proliferation and survival Survival factor for B cells Induced by interferon type 1 and type 2 Co-stimulates immune B cell responses
What is BLyS?
B lymphocyte stimulator
Soluble ligand of the TNF cytokine family
Role in B cell differentiation, homeostasis and selection
BLyS levels affect survival signals and selective apoptosis of auto-antibody producing B cells
What is VEGF?
Vascular Endothelial Growth Factor
Expressed on endothelial and non endothelial cells including tumor cells
Potent angiogenic factor
Investigations in Common Variable Immunodeficiency (CVID)
IgG low - one or both of IgA/IgM also decreased
B cell count nor
Impaired vaccination response
Low switched memory B cells
Investigations in X-linked (Bruton’s) Agammaglobulinaemia
IgG levels - typically undetectable B-cell count - zero No plasma cells or germinal centres in tissue biopsies B-cell precursors present in the marrow BTK expression in flow cytometry Genetic analysis of BTK gene
Northern blotting is used for?
Detect RNA
SNOW - South - NOrth - West
DROP - DNA - RNA - Protein
Abacavir - HLA hypersensitivity
HLA-B*57:01
A derivative of abacavir binds to B57:01 within the cell - alters the repertoire of self peptides which can bind to B57:01. Presentation of altered self peptides to T cells = altered immune response
Carbamazepine - HLA hypersensitivity
HLAB*15:02
What is the role of the HLA / MHC in the immune response?
Presentation of antigens to T cells
Extracellular proteins (mainly bacteria) are processed through phagocytosis, phagolysomes onto MHC II = CD4+ T cells
Cytosine proteins made by the cell are processed via the golgi onto MHC I = CD8+ T cells (mainly viral response)
Distribution of HLA / MHC?
MHC I - present on membrane of all nucleated cells (except RBCs)
MHC II - present on APCs: dendritic cells, B cells and macrophages
What is the main purpose of somatic hypermutation in B cells?
Selection of high affinity B cells
Absence of B cells is characteristic of which primary disorder?
X-linked agammaglobulinaemia (XLA)
Immunoglobulins are produced by plasma cells, which themselves are the result of the development & differentiation of B cells
Which disease is caused by decreased apoptosis resulting in increased presentation of self antigen?
SLE
The mediators of SLE are autoantibodies and the immune complexes they form with antigens
Cancers related to Common Variable Immunodeficiency Disease (CVID)
Non-Hodgkins lymphomas
Cancer’s related to Hyper-IgE syndrome (Job’s syndrome)
Aggressive B cell lymphomas
May be linked to abnormalities in STAT3 / IL-21 dependent differentiation of B cells
Activation of classical complement pathway?
Binding of C1q in the C1 complex to the Fc portion of IgG or IgM immune complexes
Activation of the leptin complement pathway?
Mannose-binding lectin binding to sugar moieties on the surface of pathogens leading to the engagement of proteases (analogous to Cr1 and C1s of the classical pathway)
Activation of alternative complement pathway?
Does not require antibody or contact with a microbe to become activated. C3 is constantly autoactivated at a low level, a process that is rapidly amplified in the presence of a microbe / damaged host cell / lack of a complement regulatory protein
Goal of the 3 complement cascades?
Deposition of C3b on a target (opsonisation), which marks it for elimination
Also leads to the release of pro inflammatory anaphylatoxins (C3a and C5a) and assembly of the membrane attack complex (MAC)
Diseases associated with deficiencies in C3-C9
Pneumococcal & influenza - C3 deficiency
Neisserial infections - C5, C6, C7, C8 or C9 deficiency
3 stages of Tcell development
- Migration to thymus
- T cell receptor gene rearrangement
- Selection = learn to respond to MHC
Selection of T cells
Need to be useful: positive selection - choose T cells that can interact with MHC
Can’t be useless: death by neglect - ignore T cells that cannot interact with MHC
Can’t be harmful: negative selection - delete self reactive T cells
Turn harmful to useful: induce Treg cells from self reactive T cells
3 signal model of T cell activation
Signal 1: Ag peptides presented by MHC
Signal 2: co-stimulation (CD40 / 80 / 86)
Signal 3: Th subset preference (Th 1 / Th2 / Th17 / Treg)
What is the critical step in central T cell tolerance?
Negative selection
Role of AIRE?
AIRE is a transcription factor expressed in the medullary of the thymus
Is part of the mechanism which eliminates self reactive T cells - i.e. drives negative selection
Recurrent infection suggestive of a T cell immunodeficiency?
Intracellular organism infections
- Fungi e.g. mucosal candida, pneumonitis
- viruses e.g. CMV, VZV, HSV, Protozoa (CD8)
- Listeria
Mechanism of Hereditary Angioedema
Due to deficiency (Type 1) / dysfunction (Type 2) of C1 esterase inhibitor - leads to increased levels of bradykinin (a potent vasodilatory peptide) and uncontrolled activation of the complement pathway (consumption of C4 through loss of C1r and C1s).
Due to mutations in the SERPING1 gene
Type one is more common
Treatment: Icatibant (bradykinin B2 receptor antagonist)
Investigations for Hereditary angioedema
Suggestive history and physical findings
C4 level
C1 inhibitor level low or abnormal function
Genetic testing not usually required
Role of conjugate vaccine attached to a carrier protein AND polysaccharide antigen?
Better efficacy due to better T cell response
Addition of the carrier protein to a polysaccharide vaccine makes a polysaccharide vaccine T cell dependent thus boosting the effect of the vaccine
Role of IL-12?
Promotes formation of Th1 cells
Role of Th1
Secretes IFN-gamma, TNF, lymphotoxin
Prevents intracellular organisms (e.g. mycobacteria, listeria, toxoplasma, leishmania)
Role of IFN-gamma
Activates macrophages
Activates NK cells
Acts on B cells to stimulate Ab formation
Defence against intracellular pathogens (viruses & intracellular bacteria)
Role of Th2?
Differentiate in response to IL-4 Secrete IL-4, IL-5, IL-6, IL-10, IL-13 Activates B cells to make neutralising antibodies Role in inducing ‘atopic’ type response - IgE production by B cells (IL-4, 13) - Eosinophils (IL-5) Defence against helminths
Role of Th17?
Differentiate in response to IL-1, IL-6, IL-23
Secrete IL-17 and IL-22
Defence against Candida, staphylococcus
Role of Treg?
Secretes cytokines (Is-10, TGF-beta) with immunosuppressive properties
Cardinal feature of the innate immune system?
Inflammation
What is CRP?
Acute phase protein that binds to phospholipid in foreign pathogens or damaged host cells
Can promote the recognition and elimination of pathogens and enhance clearance of apoptotic and necrotic cells
Diseases associated with lack of complement components
Classical pathway
- C1q, C1r, C1s: SLE
- C4: SLE, GN
- C2: SLE, vasculitis, GN, recurrent pyogenic infections
- C3: recurrent pyogenic infections, CN, immune complex diseases
Alternative pathway
- Properdin, factor D: Neisseria infections
Terminal components
- C5/6/7/8/9: disseminated Neisseria infections
Examples of Live Attenuated Vaccines?
BCG MMR Oral rotavirus Oral polio Yellow fever Oral typhoid Varicella
Contraindications to yellow fever vaccine?
Anaphylaxis to previous dose
Anaphylaxis to eggs
HIV withCD4 count <200
Thymus disorder e.g. myasthenia gravies, thymoma, thymectomy, DiGeorge syndrome
Haematopoetic stem cell transplant recipients
Pregnant women
Breastfeeding infant <9 months old
Most important event in complement dependent cytotoxicity
Formation of membrane attack complex
Paracetamol hypersensitivity
A weak inhibitor of COX1
The majority of suspected paracetamol reactions occur in conjunction with NSAID intolerance and relate to the pharmacological action of COX1 inhibition
REMEMBER: cyclooxygenase inhibition blocks the conversion of arachidonic acid to prostaglandins and thromboxane resulting in a therapeutic anti-inflammatory effect
What is haemophagocytic lymphohistiocytosis (HLH)?
Syndrome of excessive inflammation and tissue destruction due to abnormal immune activation
NK cells and / or cytotoxic lymphocytes fail to eliminate activated macrophages
Immunologic changes that occur in allergen immunotherapy?
- Decreases in mast cells and basophil activity and degranulation
- Changes in allergen-specific antibody isotypes
- Generation of allergen-specific regulatoryT and B cells
- Decrease in tissue mast cells and eosinophils
Highest association with fatal anaphylaxis
Poorly controlled asthma
Other risk factors for death:
Patient age
Concurrent use of ACEi and/or Beta Blockers
Dose of allergen
What is an auto inflammatory syndrome?
Autosomal dominant inherited disorders
Distinguished by absence of a defined adaptive immune response
Prototype = hereditary periodic fever syndromes; share a common involvement of certain specific cytokines e.g. IL-1 beta and TNF
Canakinumab: anti IL-1 beta
Most important costimulatory signal in naive T cells?
CD28 - binds to B7-1 and B7-2 (CD80/86) on the APC
Action of CTLA-4 on T cells ?
Inhibits activation of T cells
Indications for allergy desensitisation
IgE mediated disease
Sensitisation is relevant for the symptoms
Symptoms are of sufficient severity and duration
Availability of a standardised high-quality allergen extract of the specific allergen intended to be used for immunotherapy
Contraindications for allergy desensitisation
Malignant disease Autoimmune disease Current therapy with beta blockers Asthma patients with FEV1<70% under treatment or uncontrolled asthma Pregnancy Acute infection e.g. influenza
Indications for drug desensitisation
No alternative/ alternative inferior (e.g. syphillus in pregnancy)
No history of anaphylaxis to medication
Mechanism of calcineurin inhibitors
Ciclosporin and Tacrolimus form complexes with cytoplasmic immunophilims (cyclophilin and FKBP-12 respectively) which block the action of calcenurin in activates cells. This prevents production of IL-2 (which normally stimulate T cell proliferation and differentiation)
AE: hypertension, nephrotoxicity, gum hyper trophy
Mechanism of Azathioprine
Metabolised to
- 6-mercaptopurine: inhibits de novo purine synthesis
- Thioguanine: anti proliferative effect on mitotically active lymphocyte populations; inhibits CTL/NK cells; induces apoptosis of T cells via Rac1 gene
Mechanism of glucocorticoids
Bind to glucocorticoid receptor - translate to nucleus- alters transcription and intercepts secondary messengers Inhibits synthesis / release of - cytokines (IL-1, TNF, IL-2, IFN-gamma) - prostaglandins, leukotrienes - plasminogen activator Non selective
Presentation of Takayasu’s arteritis
Young women <40 years Limb claudication Decreased brachial artery pulse Differential limb SBP >10mmHg Subclavian artery or aortic bruit Abnormal angiogram
Gold standard for diagnosis = angiogram (beading, stenosis, aneurysms)
Mechanism of mycophenolate
Converted to mycophenolic acid, which selectively suppresses lymphocyte proliferation and antibody formation by inhibition of inosine monophosphate dehydrogenase
Depletion of guanosine nucleotides (required for de novo purine synthesis in lymphocytes) results
= G1 arrest
Mechanism of methotrexate
Inhibits dihydrofolate reductase = essential for DNA synthesis
Mechanism of Cyclophosphamide
Alkylating agent - alters DNA
Cell cycle inhibitor
Cytotoxic effects on lymphocytes = Lymphocytopenia (B>T cells)
Mechanism of abnormal phagocytise cell function in chronic granulomatous disease?
Failure to produce reactive oxygen intermediates
CGD: Diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds to kill certain ingested pathogens.
Phagocytes require the enzyme ‘phagocyte NADPH oxidase’ to produce reactive oxygen species to destroy ingested bacteria
Role of transforming growth factor (TGF) beta?
Immunosuppressive cytokine
Implicated in Treg function
Cell type playing the predominant role in the early inflammatory phase of an IgE mediated allergic response?
Mast cells involved in early inflammatory phase
Eosinophils involved in late inflammatory phase
What interaction will lead to septic shock in gram negative sepsis?
Binding of Toll Like Receptor 4 to bacterial lipopolysaccharides
Variation in which cell surface molecule is capable of conferring the greatest resistance to HIV infection?
Chemokine receptor CCR5
Clinical features of chronic granulomatous disease?r
Recurrent infections with coagulase negative bacteria and fungi
Staphylococcus infection of the skin
Purulent dermatitis
Aspergillus pneumonia
What NOD-like receptor is responsible for the acute inflammation seen in gout?
NALP3
Urate crystals and calcium pyrophosphate dehydrate (CPPD) activates the NALP3 inflammation. Caspase 1 is activated and IL-1 beta is released causin inflammation and pain
Severe Combined Immune Deficiency
Features produced by the loss of expansion of Lymphoid Progenitor Cells (‘alymphocytosis’)
What cell surface molecule is least important in the regulation of NK cell function?
MHC class II on the target cell
What is a T dependent antigen?
Antigens that do not directly stimulate the production of antibody without the help of T cells
E.g. Proteins
What is a T independent antigen?
Antigens which can directly stimulate the B cells to produce antibodies without T cell help
E.g. polysaccharides, dextran, lipopolysaccarides, peptidoglycans
Which immunoglobulin binds with low affinity and high avidity when exposed to antigen?
IgM
Affinity- overall strength of the bond between antibody and antigen
Avidity - overall strength of the interaction between antibody and antigen
IgM is a pentameter therefore has the highest avidity
Treatment of hereditary angioedema
C1-inhibitor concentrate
Danazol
3 cardinal features of Autoimmune Polyendocrine Syndrome Type 1?
- Chronic mucocutaneous candidiasis
- Autoimmune hypo parathyroidism
- Autoimmune Addison’s disease + other autoimmune manifestations
IPEX
Lack of foxP3 means no Treg cells = global overactivity of immune function Immune dysfunction Polyendocrinopathy Enteropathy X-Linked
Primary IgA deficiency
Most common primary immune disorder
High incidence of atopy and food allergy
Associated with IBD, RA, SLE, Sjogrens, ITP
Patients at increased risk of transfusion reactions due to presence of Anti-IgA antibodies
Ix: absent IgA, normal B cell count
Rx: NOT IVIG, antibiotics for acute episodes
The polymeric Ig receptor (PIgG) transports predominately which class of immunoglobulin into the mucosal lumen?
IgA
Cross reacting foods in patients with latex allergy?
Banana, avocado, kiwi, chestnut
Papaya, fig, potato, tomato
Clinical manifestations is CVID
Recurrent sinopulmonary infections Chronic diarrhoea, malabsorption Skin infections Autoimmunity e.g. ITP, RA, thyroid disease, vitiligo Neoplasia (400x risk of NHL) Food allergies Bronchiectasis and respiratory failure
Ciclosporin: adverse effects
Nephrotoxicity
Hypertension
Neurotoxicity: tremor, headache, confusion, seizures, coma, psychosis
HUS
Mycophenolate: adverse effects
D / N / V / abdominal pain
Abnormal LFTs
Leucopenia, neutropenia, anaemia, thrombocytopenia, pancytopenia
Mechanism of Sirolimus
mTOR inhibitor
Following entry into the cytoplasm, sirolimus binds to the FK binding protein to modulate the activity of mTOR - inhibits IL-2 = cell cycle arrest in G1-S phase
Also blocks the response of T and B cell activation by cytokines, which prevents cell cycle progression and proliferation
AE: hyperlipidemia via inhibition of lipoprotein lipase
Cyclophosphamide toxicity
Infertility secondary to gonadal toxicity Malignancy Bladder toxicity Myelosuppression Herpes Zoster Major infection
Mycophenolate toxicity
GI upset Leukopenia Thrombocytopenia Anaemia Infection Malignancy
Low serum complement level systemic diseases
SLE Sub acute bacterial endocarditis Visceral abscess Shunt nephritis Cryoglobulinaemia Acute post infectious GN MPGN
Normal serum complement level systemic diseases
Polyarteritis nodosa Hypersensitivity vasculitis Wagner’s HSP Goodpasture Syndrome IgA nephropathy RPGN Anti GBM disease Immune complex disease
Mechanism for hypokalemia in a patient who develops metabolic alkalosis secondary to vomiting?
Increased intracellular exchange of potassium for hydrogen
Metabolic alkalosis causes K movement into cells
GATA2 deficiency
Syndrome of monocytopenia and mycobacterial diseased
Characterised by late childhood/ adult onset of disseminated nontuberculosis disease or disseminated fungal disease
Monocytopenia, NK cell cytopenia, B cell lymphopenia
CD 40 ligand is primarily expressed on?
Activated CD4+ T helper cells
HLA-A3 association
Haemochromatosis
HLA-B5
Bechet’s disease
HLA-DQ2/DQ8
Coeliac disease
HLA-DR2
Narcolepsy
Good pastures
HLA-DR3
Dermatitis herpetiformis
Sjogrens
Primary biliary cirrhosis
HLA-DR4
T1DM
RA
