General principles of immune response Flashcards
What are the components of the innate immune response?
Barrier and chemical mechanisms.
PRR
Cellular (phagocytes and NK cells).
What are the components of the adaptive immune response?
Humoral and cellular.
What are the main PRRs?
Toll-like receptors (TLRs)
NOD-like receptors (NLR)
RIG-like receptors (RLRs)
C-type lectins
scavenger receptors.
What are the main antimicrobial peptides associated with the innate immune system?
Defensins
Cathelin
Protegrin
Granulysin
Histatin
Secretory leukoprotease inhibitor
Probiotics.
Which immune cells are involved in the innate response?
Macrophages
Dendritic cells
NK cells
NK-T cells
Neutrophils
Eosinophils
Mast cells
Basophils
Epithelial cells.
Which complement components are involved in the innate immune response?
Classic and alternative pathways and proteins that bind complement proteins.
What are pattern recognition receptors (PRRs)?
Inclusive term for antigen recognition receptor in innate system. Common theme is recognition of Pathogen-associated Molecular Patterns (PAMPs) but also Danger Associated Molecular Patterns (DAMP’s).
What are the two groups of PRRs?
- Cell surface (transmembrane) and intracellular receptors – TLRs, NLRs, RLR’s and CLR’s.
- Fluid-phase soluble molecules - C-type lectin
What are the main features of the C-type lectin family?
e.g. Mannose-binding Lectin
Recognition of microbial complex carbohydrates
Bind via Carbohydrate-Recognition Domains (CRDs)
Role in neutralisation of pathogen
Role in recruitment of adaptive response
What is the role of IL-1?
Endothelia
- increased coagulation
- increased inflammation
Hepatocytes
- increased acute phase proteins
Hypothalamus
- increased fever
What is the role of TNF?
Endothelia
- increase coagulation
- increased inflammation
Hepatocytes
- increase acute phase proteins
Neutrophils
- increase activation
Hypothalamus
- increased fever
What is the role of IL-6?
Hepatocytes
- acute phase proteins
B lymphocytes
- increased proliferation
What is the role of macrophages?
Phagocytose and kill bacteria
Produce antimicrobial peptides
Bind (LPS)
Produce inflammatory cytokines.
What are the roles of plasmacytoid dendritic cells (DCs)?
Produce large amounts of interferon- (IFN-) which has antitumor and antiviral activity, and are found in T cell zones of lymphoid organs; they circulate in blood.
What are the roles of NK cells?
Kill foreign and host cells that have low levels of MHC+ self peptides.
Express NK receptors that inhibit NK function in the presence of high expression of self-MHC.
What are the roles of myeloid dendritic cells?
Interstitial DCs
- strong producers of IL-12 and IL-10
- located in T cell zones of lymphoid organs
- circulate in blood
- present in the interstices of the lung, heart, and kidneys.
Langerhans DCs
- strong producers of IL-12
- located in T cell zones of lymph nodes, skin epithelia, and the thymic medulla
- circulate in blood.
What are the roles of neutrophils?
Phagocytose and kill bacteria, produce antimicrobial peptides.
What is the role of eosinophils?
Kill invading parasites.
What are the roles of mast cells of basophils?
Release TNF-, IL-6, IFN- in response to a variety of bacterial PAMPs.
What are the roles of epithelial cells?
Produce anti-microbial peptides
- tissue specific epithelia produce mediators of local innate immunity, e.g. lung epithelial cells produce surfactant proteins (proteins within the collectin family) that bind and promote clearance of lung invading microbes.
What are the central features of the adaptive immune response?
Evolution in response to changing pathogen structures.
Unique antigen receptor found on each lymphocyte. In response to infection this lymphocyte undergoes clonal expansion.
What are the primary lymphoid organs and what is their function?
Bone marrow (B cells) and thymus (T cells). Responsible for lymphocyte development and selection.
What are the secondary lymphoid organs and what is their function?
Spleen, lymph nodes and mucosal surfaces. Take part in immune response.
What is the range of antigenic variability estimated to be?
10^9
How do the T and B cell receptors generate receptor diversity?
Recombination of the variable segments of the gene (V,D and J). Splicing together.
What is the mechanism of Ag presentation for MHCII?
Antigens are internalised
Broken down to peptides
Peptides associate with newly synthesised Class 2 molecules and are brought to the cell surface.
If the peptides are foreign they are recognised by helper T cells which are then activated.
Helper T cells produce cytokines needed by B cells, T cells , etc.
Which cells do MHCI proteins present to?
Cytotoxic T cells (CD8).
Which cells do MHCII proteins present to?
Helper T cells (CD4).
What are he functions of antibodies?
Precipitation of dissolved antigens, neutralization, agglutination and activation of complement.
What are the cytokines of adaptive immunity?
IL-4
IL-5
IL-12
IL-13
IL-17
INF gamma
What is immunosupression?
Immunosuppression: a natural or artificial process which turns off the immune response, partially or fully, accidentally or on purpose.
What is immunodeficiency?
The lack of an efficient immune system-susceptibility to infections.
What are the potential uses of immunosuppression?
Transplant rejection, autoimmunity and lymphoproliferative diseases.
What might be the consequences of immunosuppression/immunodeficiency?
Loss if PRRs (pneumococcus, HSV)
Loss of macrophages/neutrophils (CGD, staph, aspergillus)
Loss of complement (meningococcus)
Loss of cytokines (mycobacterium)
Loss of B cells, (recurrent sino-pulmonary infections),
Loss of T-effector cells (SCID, opportunistic infections).
What is hypersensitivity?
Undesirable, damaging, discomfort-producing and sometimes fatal reactions produced by the normal immune system (directed against innocuous antigens) in a pre-sensitized (immune) host.
What are the features of type 1 (anaphalactic) hypersensitivity?
Immunopathogenesis -IgE Ab mediated mast cell and basophil degranulation- release of preformed and de novo synthesized inflammatory mediators
Clinical features -Fast onset (15-30 min). Weal and flare.
Can have 2nd phase (late) response
Common antigens - Pollen, bee venom, animal dander
Associated diseases - Hay fever, allergic asthma
What is the mechanism behind type 1 hypersensitivity?
IgE mediated
Cross-linking of FceR by allergen
Release of pre-formed mediators e.g. histamine
Synthesis of lipid mediators e.g. leukotrienes
What are the features of IgE?
Produced by plasma cells from class-switched B cells under the control of IL-4 and CD40L - CD40 interaction
Extremely low serum levels BUT
High affinity receptor for IgE (FceRI) on mast cells and basophils
Permits stable binding over long periods
What is the early phase response?
MAST CELL
- FceR1 present at high density
- Cross-linking of FceR1 by allergen leads to activation of mast cell, resulting in :-
DEGRANULATION - Release of pre-formed mediators
SYNTHESIS OF LIPID MEDIATORS
What are the functions of histamine?
Stimulation of irritant nerve receptors
Smooth muscle contraction
Increase in vascular permeability
What is the function of kallikrein?
Activates bradykinin - similar actions to histamine.
What are the pre-formed mediators?
Histamine, kallikrain and tryptase.
What are the lipid mediators?
Arachidonic acid derivatives - leukotrines and prostoglandins (thromboxane)
What are the features of the late phase response?
BASOPHILS -Similar properties to mast cells over longer time scale
EOSINOPHILS - GRANULES contain cytotoxic proteins (e.g. Eosinophil Cationic Protein)
Attracted to sites of allergic inflammation by chemokines (e.g. Eotaxin 1/2) In tissues, RELEASE CONTENTS OF GRANULES - major source of tissue damage in allergic response.
T CELL RESPONSES
Involved in both EARLY and LATE response to allergen
Cytokine production by activated T cells critical in ongoing response
CYTOKINE-DRIVEN ACTIVITY is the major source of PATHOGENESIS in allergic responses
What are the features of type 2 hypersensitivity?
Antibody-mediated cytotoxic reactions
Binding of antibody to target antigen on cell membrane results in
- Activation of the complement cascade resulting in cell lysis
- Aggregation of Fc portions of immunoglobulin/C3b with binding to FcRs/C3bR resulting in opsonisation, phagocytosis & destruction
Initiated by IgM or complement-binding IgG
- IgM»_space; IgG1
- IgM most efficient since pentavalent
- IgG requires multiple binding
Cells usually affected are haematopoietic cells
Give examples of type 2 hypersensitivity.
Blood group incompatibility
Autoimmune haemolytic anaemias
Affecting neutrophils
Affecting platelets
What is type 3 hypersensitivity?
IMMUNE COMPLEX REACTIONS
- IgG + Ag = AgAb complex
- FcR in complex bind C1q
- Complement activation leads to generation of activated complement fragments
4a. C5a - attractant for neutrophils
4b. C3b - Opsonin - Attempted phagocytosis of complexes - release of enzymes, oxygen radicals
- Consequence is tissue damage
e. g. Farmer’s lung
Give other examples of antibody-mediated immunopathology.
Direct inactivation - e.g. intrinsic factor -> B12 deficiency
Indirect inactivation - binding to e.g. hormone results in clearance of Ab/Ag complex
Receptor blockade - e.g. to AChR in Myasthenia Gravis
What is the mechanism behind contact dermatitis?
e.g. Nickel, poison Ivy
Combination of DTH and cytotoxic reaction
Nickel acts as hapten with epidermal proteins
Antigen presentation by APC
Keratinocytes may present to CTL precursors
What is a granulomatous reaction?
Focal collections of inflammatory cells in tissues -Macrophages, epithelioid cells (phagocytic cells containing foreign material), giant cells, lymphocytes
T cells are Th1-type - secrete IL2 & IFNg
Release of IL-12 by macrophages critical in initiation of response
What is the difference between tuberculoid and lepromatous Leprosy?
Tuberculoid is Th1 weighted - protective.
Lepromatous is Th2 weighted - non-protective
Give examples of granulomatous diseases.
Mycobacterial infections
Sarcoidosis
Wegener’s granulomatosis
Crohn’s.
