L5&6- Immunopathology Flashcards
general overview of Innate immune system
Innate:
-Barrier and chemical mechanisms
- PRR (Pattern recognition receptor) - proteins expressed by cells to identify two classes of molecular patterns: 1) pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and 2) damage-associated (DAMPs), which are associated with cell components that are released during cell damage or death.
- Phagocytes, natural killer cells
General overview of adaptive immune system
Humoral
Cellular
Pattern recognition receptors
Antigen recognition receptor in innate system
Common theme is recognition of Pathogen-associated Molecular Patterns (PAMPs) but also Danger Associated Molecular Patterns (DAMP’s)
2 groups
- Cell surface (transmembrane) and intracellular receptors – TLRs, NLRs, RLR’s and CLR’s
- Fluid-phase soluble molecules
FLUID-PHASE RECOGNITION MOLECULES
C-TYPE LECTIN FAMILY
- COLLECTINS
- Mannan-binding Lectin
- Surfactant Protein A & D
Role in neutralisation of pathogen
Role in recruitment of adaptive response
Steps of Classical Pathway
Antigen+Antibody Complex –> c1, c4, c2 —> C3 convertase
From C3 convertase can go 3 ways:
1) c3a, c5a –> peptide mediators of inflammation, phagocyte recruitment
2) c3b –> binds to complement receptor on phagocyte —>opsonisation of pathogens —> removal of immune complexes
3) c3b —> c5b, c6, c7 ,c8 ,c9 —> Membrane attack complex, lysis of certain pathogens and cell
What is opsonization
An immune process where particles such as bacteria are targeted for destruction by an immune cell known as a phagocyte .
The process of opsonization is a means of identifying the invading particle to the phagocyte
Function of macrophages
Phagocytose and kill bacteria; produce antimicrobial peptides; bind (LPS); produce inflammatory cytokines
Function 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.
Function of Myeloid dendritic cells
Interstitial DCs are strong producers of IL-12 and IL-10
Langerhans DCs are strong producers of IL-12
function of Natural killer (NK)
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
Function of NK-T cells
Lymphocytes with both T cell and NK surface markers that recognize lipid antigens of intracellular bacteria such as M. tuberculosis by CD1 molecules and kill host cells infected with intracellular bacteria.
Function of Neutrophils
Phagocytose and kill bacteria, produce antimicrobial peptides
Function of Mast cells and basophils
Release TNF-, IL-6, IFN- in response to a variety of bacterial PAMPs
Function of Epithelial cells
Produce anti-microbial peptides; tissue specific epithelia produce mediator 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
ADAPTIVE IMMUNE RESPONSE
Evolution in response to changing pathogen structures
In response to infection this lymphocyte undergoes CLONAL expansion
High degree of specificity
VDJ recombination enables multiple immunoglobulin structures
Mechanism of antigen presentation
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.
FUNCTIONS OF CLASS 1 MHC
The function of these proteins is to present antigenic peptides to T cells- T cells only see antigen in association with MHC Proteins.
MHC class 1 proteins present peptides to cytotoxic T cells
FUNCTIONS OF CLASS 2 MHC
The function of these proteins is to present antigenic peptides to T cells- T cells only see antigen in association with MHC Proteins.
MHC Class 2 proteins present peptides to helper T cells
Lymphocytes-function: B lymphocytes
develop potential to secrete antibodies: humoral immunity
Lymphocytes-function: T lymphocytes
Killer or cytotoxic T lymphocytes are able to kill. Cellular immunity
Helper T lymphocytes secrete growth factors (cytokines) which control immune response: Help B lymphocytes and T lymphocytes (Helper T cells are target of HIV)
Suppressor T lymphocytes may damp down immune response
Binding of antibodies to antigens inactivates the antigens by…?
Neutralization (blocks binding sites, coats bacteria)
Agglutination of microbes
—> Phagocytosis
Activation of complement —> cell lysis
What happens when cytotoxic t cell binds to foreign antigen?
Recognises non self antigen –> binds to infected cell –> Releases Perforin (hole forming) enzyme that can promote apoptosis –> infected cell destroyed
IL2
T cell growth factor (and IL 15)
Do we need to know the different cytokines for adaptive and innate immunity?
I don’t know? :s
Immunosuppression
A natural or artificial process which turns off the immune response, partially or fully, accidentally or on purpose
Uses:
Transplant rejection
Autoimmune diseases
Lymphoproliferative diseases
Immunodeficiency
the lack of an efficient immune system-susceptibility to infections
What pathogen can affect PRR (e.g TLR)?
Pneumococcus
HSV
What pathogen can affect the Complement pathway?
Meningococcus
What disorder can affect white blood cells or cause the absence of them?
SCID
Opportunistic infections
What would affect release of cytokines?
Mycobacterium
What type of infections what result in poor antibody response?
Recurrent Sino-pulmonary infections
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
HYPERSENSITIVITY TYPES
TYPES I - IV
I - IgE MEDIATED REACTION
II - CYTOTOXIC REACTION
III - IMMUNE COMPLEX REACTION
IV - CELL MEDIATED REACTION (DTH)
Type I (anaphylactic) Hypersensitvity
Immunopathogenesis:
IgE Ab mediated mast cell and basophil degranulation- release of preformed and inflammatory mediators
Clinical features:
Fast onset (15-30 min)
Weal and flare
Early phase and late phase
Common antigens:
Pollen, bee venom, animal dander
Associated diseases:
Hay fever, allergic asthma
IMMUNOGLOBULIN E
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
PRE-FORMED MEDIATORS
HISTAMINE
Stimulation of irritant nerve receptors
Smooth muscle contraction
Increase in vascular permeability
KALLIKREIN
Activates bradykinin - similar actions to histamine
LIPID MEDIATORS
ARACHIDONIC ACID DERIVATIVES
Arachidonic acid –> (Lipoxygenase) –>Leukotrienes
Arachidonic acid–> (cycloxygenase) –>Prostaglandins (e.g:PROSTACYLINE, THROMBOXANE )
Late phase responses Type 1 hypersensitivity
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)
Late phase responses Type 2 hypersensitivity
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
EXAMPLES OF ALLERGIC DISEASES
ASTHMA
RHINITIS
DERMATITIS
FOOD ALLERGY
What happens in HYPERSENSITIVITY - TYPE II
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
Causes of HYPSERSENSITIVITY - TYPE II
Initiated by IgM or complement-binding IgG
IgM»_space; IgG1 & IgG3
IgM most efficient since pentavalent
IgG requires multiple binding
Cells usually affected are haematopoietic cells e.g:
- Blood group incompatibility
- Autoimmune haemolytic anaemias
- Affecting neutrophils
- Affecting platelets
HYPERSENSITIVITY - TYPE III
IMMUNE COMPLEX REACTIONS
1. 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
Examples of HYPERSENSITIVITY - TYPE III
Vasculitis
Nephritis
Arthritis
Farmer’s lungs
OTHER ANTIBODY-MEDIATED IMMUNOPATHOLOGY
Inactivation:
- Direct
e. g. to Intrinsic factor - B12 deficiency
-Indirect
binding to e.g. hormone results in clearance of AgAb complex
- Receptor blockade
e. g. To AChR in Myasthenia Gravis
HYPERSENSITIVITY - TYPE IV
T cell mediated - CD4+ cells (MHC class II)
- Delayed type e.g. Tuberculin skin reaction
- Initially perivascular infiltration of lymphocytes & monocytes
- LANGERHAN’S cells present neo-antigen to T cells
- Ag-specific T cells release cytokines - recruitment of macrophages (non Ag-specific)
- Activated macrophages cause tissue damage
- Requires previous exposure to antigen
OTHER CELL-MEDIATED IMMUNOPATHOLOGY
T cell-mediated cytotoxicity
CD8+ T cells (MHC Class I)
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
GRANULOMATOUS REACTIONS
Granulomas:
- 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
GRANULOMATOUS DISEASES
Infections:
- Mycobacterial
- Tuberculosis
- Atypical mycobacteria
- Leprosy
- Tuberculoid - Th1 - Protective
- Lepromatous Th2 - Non-protective
Unknown aetiology:
- Sarcoidosis
- Wegener’s Granulomatosis
- Crohn’s disease
