L5&6- Immunopathology Flashcards Preview

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Flashcards in L5&6- Immunopathology Deck (49):
1

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

2

General overview of adaptive immune system

Humoral

Cellular

3

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

4

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

5

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

6

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

7

Function of macrophages

Phagocytose and kill bacteria; produce antimicrobial peptides; bind (LPS); produce inflammatory cytokines

8

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.

9

Function of Myeloid dendritic cells

Interstitial DCs are strong producers of IL-12 and IL-10

Langerhans DCs are strong producers of IL-12

10

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

11

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.

12

Function of Neutrophils

Phagocytose and kill bacteria, produce antimicrobial peptides

13

Function of Mast cells and basophils

Release TNF-, IL-6, IFN- in response to a variety of bacterial PAMPs

14

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

15

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

16

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.

17

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

18

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

19

Lymphocytes-function: B lymphocytes

develop potential to secrete antibodies: humoral immunity

20

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

21

Binding of antibodies to antigens inactivates the antigens by...?

Neutralization (blocks binding sites, coats bacteria)

Agglutination of microbes

---> Phagocytosis

Activation of complement ---> cell lysis

22

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

23

IL2

T cell growth factor (and IL 15)

24

Do we need to know the different cytokines for adaptive and innate immunity?

I don't know? :s

25

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

26

Immunodeficiency

the lack of an efficient immune system-susceptibility to infections

27

What pathogen can affect PRR (e.g TLR)?

Pneumococcus
HSV

28

What pathogen can affect the Complement pathway?

Meningococcus

29

What disorder can affect white blood cells or cause the absence of them?

SCID
Opportunistic infections

30

What would affect release of cytokines?

Mycobacterium

31

What type of infections what result in poor antibody response?

Recurrent Sino-pulmonary infections

32

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

33

HYPERSENSITIVITY TYPES

TYPES I - IV

I - IgE MEDIATED REACTION

II - CYTOTOXIC REACTION

III - IMMUNE COMPLEX REACTION

IV - CELL MEDIATED REACTION (DTH)

34

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

35

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

36

PRE-FORMED MEDIATORS

HISTAMINE
Stimulation of irritant nerve receptors
Smooth muscle contraction
Increase in vascular permeability

KALLIKREIN
Activates bradykinin - similar actions to histamine

37

LIPID MEDIATORS

ARACHIDONIC ACID DERIVATIVES

Arachidonic acid --> (Lipoxygenase) -->Leukotrienes

Arachidonic acid--> (cycloxygenase) -->Prostaglandins (e.g:PROSTACYLINE, THROMBOXANE )

38

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)

39

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

40

EXAMPLES OF ALLERGIC DISEASES

ASTHMA

RHINITIS

DERMATITIS

FOOD ALLERGY

41

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

42

Causes of HYPSERSENSITIVITY - TYPE II

Initiated by IgM or complement-binding IgG
IgM >> 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

43

HYPERSENSITIVITY - TYPE III

IMMUNE COMPLEX REACTIONS
1. IgG + Ag = AgAb complex

2. FcR in complex bind C1q

3. Complement activation leads to generation of activated
complement fragments

4a. C5a - attractant for neutrophils
4b. C3b - Opsonin

5. Attempted phagocytosis of complexes - release of enzymes, oxygen radicals

6. Consequence is tissue damage

44

Examples of HYPERSENSITIVITY - TYPE III

Vasculitis
Nephritis
Arthritis
Farmer's lungs

45

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

46

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

47

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

48

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

49

GRANULOMATOUS DISEASES

Infections:
-Mycobacterial
-Tuberculosis
-Atypical mycobacteria
-Leprosy
-Tuberculoid - Th1 - Protective
-Lepromatous Th2 - Non-protective

Unknown aetiology:
-Sarcoidosis
-Wegener’s Granulomatosis
-Crohn’s disease