VIVA: Pathology - Immunity Flashcards
Where are B lymphocytes located?
4/5 to pass:
- Bone marrow
- Circulating
- Lymph nodes
- Spleen
- Peripheral lymphoid tissue
How do B cells respond to antigenic stimulation?
Specific receptor complex (IgM)
Transformation to plasma cell
Production of specific immunoglobulins
How are B cells activated in a graft vs host reaction?
CD4+ T helper cells
Cytokines (IL-4, IL-5)
B cell stimulated by antigen in presence of cytokines
What are the normal barriers to infection by ingested pathogens in gastrointestinal tract?
3/7 to pass:
- Acid gastric secretions
- Viscous mucosal layer
- Lytic pancreatic enzymes
- Bile detergents
- Secreted IgA antibodies
- Competition for nutrients with commensal bacteria
- Clearance by defecation
Describe the barriers to infection that exist within the respiratory tract
2/4 to pass:
- Mucociliary blanket within upper airways for trapping large microbes
- Coughing (clears microbes from trachea)
- Ciliary action within trachea and large airways (moves them up to be swallowed)
- Alveolar macrophages or neutrophils attack and destroy microbes
What processes can disrupt the normal protective mucociliary action?
3/6 to pass:
- Smoking
- Cystic fibrosis (viscous secretions)
- Aspiration of stomach contents
- Trauma of intubation
- Viral infection
- Bacterial infection
What are the major classes of lymphocytes?
B lymphocytes
CD4+ T helper lymphocytes
CD8+ cytotoxic T lymphocytes
Natural killer cells
What is the role of each class of lymphocytes in the normal immune system?
Adaptive immunity:
- Circulate widely and re-circulate (especially T cells)
- Respond to foreign substances and other antigens
- Can become effector or memory cells
B cells (humoral immunity):
- Recognise antigen via transmembrane IgM/IgD
- Differentiates into plasma cell which secrets Ig
- B cells also have complement receptors, Fc receptors, CD40
T cells (cell-mediated immunity):
- Antigen-specific T cell receptor
- Binds to Ag on cells (on MHC molecules on APCs)
- Activates cell depending on type
- CD4+ / T helper cells recognise class II MHC bound Ag -> cytokine release -> macrophage activation, inflammation and B cell stimulation
- CD8+ / T cytotoxic cells recognise class I MHC bound Ag -> destruction of infected cell
NK cells:
- Kill infected and tumour cells
- No prior exposure needed
- Healthy cell class I MHC inhibits natural killer cell
- Can also secrete cytokines to contribute to inflammatory response
*need B-humoral + concept, and T-cell-mediated + concept to pass
Outline the sequence of events in type 1 hypersensitivity
- Initial antigen exposure
- Dendritic cells present antigen to T helper cells
- T helper cells differentiate into TH2 cells
- TH2 cells release cytokines that cause B cells to produce IgE
- IgE binds to mast cells
- On repeated exposure, antigen binds to and cross-links with IgE on mast cells, leading to activation of mast cells and release of:
- Vasoactive mediators (e.g. histamine, proteases, chemotactic factors; immediate)
- Lipid mediators (e.g. leukotrienes, complement, prostaglandins, platelet-activating factor; immediate)
- Cytokines (e.g. TNF; late-phase) - Action of mediators on end organs results in clinical manifestations of anaphylaxis (vasodilation, vascular leakage, smooth muscle spasm)
*need initial and repeated Ag exposure, IgE and mast cell degranulation to pass
What are the pathological changes that occur at the tissue level in type 1 hypersensitivity?
3/5 to pass:
- Vasodilation
- Increased vascular permeability
- Smooth muscle spasm (bronchospasm)
- Cellular infiltration
- Epithelial damage
What are the organ effects of an anaphylactic response?
3 to pass (from different systems):
- Overwhelming activation of type 1 hypersensitivity reaction: hypotension, hypoperfusion of organs
- Skin reactions: rashes, in some cases blisters
- Mucosal involvement: angioedema
- Respiratory tract: broncho infiltrates, bronchial smooth muscle contraction, upper airway oedema leading to airway obstruction
What characterises the late phase reaction seen in type 1 hypersensitivity?
- Ongoing inflammatory reaction without additional exposure to triggering antigen
- Characterised by infiltration of the tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells as well as tissue destruction, typically in the form of mucosal epithelial cell damage
- Time course 2-24 hrs later without additional exposure, may last for days
What are the actions of mast cell mediators in type 1 hypersensitivity? Give examples
Cellular infiltration: leukotrienes, platelet-activating factor, cytokines, other chemotactic factors
Vasoactive effects: histamine*, platelet-activating factor, leukotrienes, PGD4
Smooth muscle spasm: leukotrienes, histamine, prostaglandins, platelet-activating factor
*histamine + two others + reasonable actions needed to pass
What are the primary mediators within the mast cell granules and their actions
Biogenic amines*:
- E.g. histamine
- Intense smooth muscle contraction
- Increased vascular permeability
- Increased secretion by nasal, bronchial, and gastric glands
Enzymes*:
- E.g. neutral proteases (chymase, tryptase), acid hydrolases
- Contained in the granule matri
- Cause tissue damage and lead to generation of kinins and activated components of complement (e.g. C3a) by acting on their precursor proteins
Proteoglycans*:
- E.g. heparin, chondroitin sulfate
- Package and store other mediators in the granules
*need 2/3 with an example of each
Describe the two phases that occur in a type 1 hypersensitivity reaction
Phase 1*:
- Initial rapid reaction
- Onset within 5-30 mins and subsides within 60 mins
- Vasodilation, vascular leakage, smooth muscle spasm, glandular secretion
- Mediated by biogenic amines, enzymes (e.g. proteases), proteoglycans (e.g. heparin), cytokines
Phase 2:
- After 2-24 hrs
- Infiltration of basophils, eosinophils, neutrophils, CD4+ T cells with tissue destruction (especially mucosal)
*needed to pass + time frame + at least one mediator
List some agents that can cause type 1 hypersensitivity
Foods (e.g. peanuts, shellfish)
Drugs (e.g. penicillin)
Environmental (e.g. bee and other insect stings)
Idiopathic
What is type 2 hypersensitivity?
Hypersensitivity caused by antibodies that react with antigens present on cell surfaces or in the extracellular matrix*
Antigens can be intrinsic to the membrane or matrix, or extrinsic (e.g. drug metabolite)
*needed to pass
Describe the mechanisms involved in type 2 hypersensitivity, giving examples for each mechanism
- Opsonisation and phagocytosis*:
- IgG antibodies opsonise cells and complement activation generates C3b and C4b, which are recognised by phagocyte Fc and protein receptors -> phagocytosis and destruction of opsonised cells
- E.g. transfusion reaction, erythroblastosis foetalis, autoimmune haemolytic anaemia, agranulocytosis, thrombocytopaenia, drug reaction (when drug acts as a hapten) - Complement and Fc receptor mediated inflammation*:
- Antibodies bind to fixed tissue such as basement membranes and extracellular matrix -> complement activation generates chemotactic agent C5a, as well as C3a which together with C5a increases vascular permeability
- Polymorphonuclear cells migrate to site and are activated via their C3a and Fc receptors -> release of pro-inflammatory mediators (e.g. prostaglandins), production of lysosomal enzymes and ROS
- E.g. glomerulonephritis, vascular rejection in organ grafts, ANCA vasculitis, Goodpastures - Antibody-mediated cellular dysfunction*:
- Antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation
- E.g. myasthaenia gravis, Grave’s disease, insulin-resistant diabetes mellitus, pemphigus vulgaris, pernicious anaemia - Antibody-dependent cellular cytotoxicity*:
- IgG coats cells and effector cells such as monocytes, neutrophils, eosinophils and natural killer cells then bind and lyse cells without phagocytosis
- Role in specific diseases uncertain
*2/4 needed to pass + one example for each
Give some examples of antibody-mediated (type 2) hypersensitivity
3 to pass:
- Transfusion reaction
- Erythroblastosis foetalis
- Certain drug reactions
- Autoimmune haemolytic anaemia, thrombocytosis and agranulocytosis
- Myaesthenia gravis
- Grave’s disease
- Pemphigus vulgaris
- Glomerulonephritis (some forms)
- Vascular rejection in organ grafts
How does type 2 hypersensitivity bring about changes in cellular function?
Antibodies directed against cell surface receptors may bind to the receptors and either:
- Upregulate their function (e.g. Grave’s disease)
- Downregulate their function (e.g. myaesthenia gravis)
What is the pathogenesis of type 3 hypersensitivity?
Ig or IgM antibodies bind antigens and then induce inflammation* either directly or by activating complement
The recruited leucocytes produce tissue damage by release of lysosomal enzymes and generation of toxic free radicals
Three phases (systemic diseases):
- Formation of antigen-antibody complexes (immune complexes)* in circulation
- Deposition of immune complexes in various tissues*
- Inflammatory reaction* at site of deposition, causing tissue injury
*needed to pass
List some examples of diseases caused by type 3 hypersensitivity
2 to pass:
- Serum sickness
- SLE
- Polyarteritis nodosa
- Post-streptococcal glomerulonephritis
- Acute glomerulonephritis
- Reactive arthritis
- Arthus reaction
What symptoms or signs may patients with type 3 hypersensitivity present with?
2 to pass:
- Arthritis
- Skin lesions
- Vasculitis
- Nephritis
- Fever
What is the pathogenesis of serum sickness?
Type 3 hypersensitivity*:
- Phase 1: formation of immune complexes (protein Ag, 1/52 -> Ab -> blood -> Ag-Ab complexes)
- Phase 2: deposition of immune complexes (medium size vessels with Ag excess most pathogenic -> high-pressure filtration -> glomeruli, joints)
- Phase 3: tissue injury caused by immune complexes, acute inflammatory reaction ~day 10
IgG and IgM (complement-fixing antibody) bind to leucocyte Fc receptors
Leucocyte recruitment and activation -> release of proteases/lysosomal enzymes -> damage
Deposition, activation and consumption of complement -> decreased C3 levels -> inflammatory reaction and tissue damage
*needed to pass + 3 phases
What are some clinical features of serum sickness?
3/5 to pass:
- Fever
- Urticaria
- Arthralgia
- Lymphadenopathy
- Proteinuria
What are the common sites for immune complex deposition in type 3 hypersensitivity?
3 to pass:
- Glomeruli
- Joints
- Skin
- Heart
- Serosal surfaces
- Small blood vessels
What chemical mediators contribute to immune complex-mediated tissue injury?
- Complement cascade (classical pathway)*:
- Opsonins C3b -> phagocytosis
- C5b, C6, C7 -> chemotactic factors
- C5a, C3a -> anaphylotoxins
- MAC C5-9 -> cell lysis - Inflammatory mediators liberated from neutrophils and macrophages*:
- E.g. histamine, platelet-activating factors, prostaglandins - Hageman factor, kinins
- Oxygen free radicals
*needed to pass
What kind of antigens cause type 3 hypersensitivity?
Exogenous*:
- Foreign protein (serum sickness)
- Bacteria (endocarditis, glomerulonephritis)
- Viruses (polyarteritis nodosum)
- Parasites
- Fungi
- Drugs
Endogenous*:
- Autoimmune diseases (e.g. SLE, glomerulonephritis)
*needed to pass + two examples of each
Describe the sequence of events that leads to sympathetic ophthalmia, a type 4 hypersensitivity reaction
Injury initiated by antigen results in sensitisation of CD4+ or CD8+ T cells*:
- Retinal antigens may be transported in the lymphatics of the damaged eye
- Reaction may occur in both eyes causing a pan uveitis
- CD4+ predominant in autoimmune disease
- CD8+ in post-infectious (especially viral) reactions
May be cytokine (CD4+ TH1 or TH17 cells involved) or direct cellular (cytotoxic lymphocyte) mediated tissue injury*
*requires antigen and either cytokine or direct cellular mechanisms to pass
What tissue changes occur in type 4 hypersensitivity?
2/4 needed to pass:
- Perivascular cellular infiltrates
- Tissue oedema
- Granuloma formation
- Cell destruction
Name examples of type 4 hypersensitivity reactions
3 to pass:
- Type 1 diabetes mellitus (Ab to glutamic acid decarboxylase)
- Multiple sclerosis (Ab to myelin basic protein and proteolipid protein)
- RA (Ab to joint synovium)
- Inflammatory bowel disease (? Ab to commensal bacteria)
- Guillain Barre (? Ab to protein antigen of peripheral nerve myelin)
- Contact sensitivity dermatitis (Ab to environmental Ag, e.g. poison ivy)
- Tuberculin reaction
- Granulomatous diseases
- Viral hepatitis
Describe the tuberculin reaction
Responses of differentiated effector T cells:
- TH1 -> cytokines including IFN-y -> macrophage activation * -> inflammation
- TH17 -> chemokines and cytokines including IL-17 and IL-22 -> recruitment of neutrophils, monocytes and CD4+ T cells *
Tuberculin reaction starts at 8-12hrs, and peaks at 21-72hrs *
Cellular response includes perivascular cuffing *, endothelial hypertrophy, epithelioid cells *, and granuloma *
*3/6 needed to pass
What are the cellular events in delayed type hypersensitivity in a previously sensitised individual?
- Delayed type hypersensitivty:
- TH1 cells are activated and secrete cytokines that are responsible for the delayed type reaction, including IL-12, IFN-y, TNF, lymphotoxin and chemokines
- Results in accumulation of mononuclear cells around small veins and venules with perivascular cuffing *, increased microvascular permeability *, escape of plasma proteins * and deposition of fibrin * in interstitium
- Typical example is the tuberculin reaction - T-cell mediated cytotoxicity:
- Sensitised CD8+ T cells (cytotoxic T lymphocytes) kill antigen-bearing target cells
*2/4 needed to pass
How does delayed type hypersensitivity differ in a naive individual compared with a previously sensitised individual?
In a naive individual, CD4+ T cells differentiate into TH1 cells after recognising antigen presented on antigen-presenting cells in association with class II MHC molecules
TH1 cells can enter the circulation and remain in the memory pool of T-cells for long periods (years)
What is type IV hypersensitivity?
Cell-mediated type of hypersensitivity initiated by specifically sensitised T lymphocytes
Includes the classic delayed type of hypersensitivity reactions initiated by CD4+ (TH1) cells and direct cell mediated cytotoxicity mediated by CD8+ (CTL) cells
What is T cell mediated cytotoxicity?
- Principle pattern of response to viral infections, tumour cells and allograft rejection
- CD8+ CTLs directly kill tissue cells and antigen-presenting cells via perforin-granzyme and Fas-FasL pathways which cause apoptosis
