Immune responses to infection by encapsulated organisms Flashcards
1
Q
Recall the roles of the innate and adaptive immune systems
A
3. Immune Responses: Innate Immune System
- Immune system has evolved to deal with infectious pathogens.
- Innate immune system consists of cells/proteins that are always present in the body and ready to mobilize and fight microbes at the site of infection.
- Main components are: epithelial barriers, phagocytes, NK cells, plasma proteins, DCs
4. Immune Responses: Adaptive Immune System
- Called into action against pathogens that are able to evade/overcome innate immune defenses.
- Components normally silent, but when activated, adapt to the presence of infectious agents by proliferating and creating ways for neutralizing or eliminating the microbes.
- Two types of adaptive immune responses:
- Humoral immunity, mediated by antibodies produced by B-cells.
- Cell-mediated immunity, mediated by T-cells
2
Q
List innate immune system components
A
- epithelial barriers
- phagocytes
- DCs
3
Q
Discuss the role fo the epithelial barrier
A
6. Epithelial Barrier of Mucous Membranes
- Constitutes our main defense against infection by pathogens:
- Tight junctions between cells act as a physical barrier.
- In RT, GIT, and UT, mucus creates a physical impediment.
- Anti-microbial chemicals produced by the host (e.g., bile, enzymes, gastric acid) inhibit microbial growth.
7. Role of Epithelial Cells
- Upregulation of Pattern Recognition Receptors (PRRs) on basal surface, allowing them to recognize bacteria that have invaded the epithelial barrier:
- Basolateral surface/vacuoles: Toll-like receptors (TLRs).
- Cytoplasm: nucleotide-binding oligomerization proteins (NODs).
- This recognition triggers an influx of inflammatory cells/lymphocytes into mucosa from the bloodstream, assisting in induction of a specific immune response to antigens of infectious agent.
4
Q
Discuss the role of phagocytic cells
A
- Macrophages*: Phagocytic cells that live in tissues, abundant in:
- Lungs (interstitium and alveoli)
- Connective tissue
- Submucosal layer of the gastrointestinal tract
- Certain blood vessels in the liver (Kuppfler cells)
- Spleen
- Neutrophils/PMNs: Short-lived phagocytic cells in the blood (not typically found in healthy tissue).
- Dendritic cells* *: Found in most tissues of the body, abundant in those that are interfaces between the external and internal environments (e.g., skin, lungs, and the lining of the GIT).
*Form a critical link between innate and adaptive immunity by activating components of the adaptive immune system through the presentation of antigen, i.e., referred to as antigen-presenting cells (APCs).
Role of Phagocytes**
- Recognize/bind pathogen: Step 1.
- Ingest/internalize pathogen in the phagosome: Step 2.
- Fuse phagosome with lysosome, which contains antimicrobial chemicals that destroy pathogens without the aid of the adaptive immune response: Step 3.
- Exocytosis of cellular debris: Step 4.
14. Binding of Phagocyte to Pathogen
- Directly:
- Phagocyte PRRs (e.g., TLRs) bind to pathogen-associated molecular patterns (PAMPs)*.
- e.g., Gram-positive bacteria: peptidoglycan, teichoic/lipoteichoic acids, flagella.
- e.g., Gram-negative bacteria: lipopolysaccharide (LPS), flagella.
*Relatively invariant molecular surface structures (not found in eukaryotes) that are shared by many related pathogens - can be obscured by bacterial capsules.
15. Binding of Phagocyte to Pathogen
- Indirectly:
- Antibody mediated
- Antibody-coated pathogen bound to Fc receptors on phagocyte surface
- Antibody mediated
- Complement* mediated
- Antibody-and-complement-coated pathogen bound to Fc receptors and complement receptors (e.g., CR1) on phagocyte surface.
- *Marks foreign particles for destruction
5
Q
List the components of the adaptive immune system
A
- Bs/antibodies and Ts
6
Q
Discuss the role of T cells
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- Major population in spleen and lymph nodes.
- Typically only recognize peptide fragments presented by major histocompatibility complex II (MHCII) molecules on the surface of APCs.
- When stimulated by APCs, T-cells proliferate into:
- CD4 TH1 cells produce macrophage-activating cytokines.
- CD4 TH2 cells produce cytokines that stimulate B-cells to produce antibody.
- After a T-cell response, T memory cells persist, remembering particular antigens, thereby responding faster and more potently to re-exposure.
7
Q
Discuss the role of B cells
A
- Present in bone marrow, other lymphoid tissues (e.g., spleen, lymph nodes, tonsils, and other mucosal surfaces), and circulate in blood and lymphatic system.
- Bind intact antigens via membrane-bound antibodies, phagocytose them (i.e., are also APCs), digest them into fragments, and display them at their cell surface via MCHII molecules.
- CD4 TH2 cells bind B-cells and produce cytokines that stimulate B-cells to differentiate into:
- Plasma cells, which secrete antibodies.
- Memory B-cells, which persist, remembering particular antigens, thereby responding faster and more potently to re-exposure.
8
Q
Discuss bacterial mechanisms to evade phagocytosis
A
Bacterial Mechanisms to Evade Phagocytosis**
- prevent encounters with phagocyte: C5a peptidase and cytolytic toxins
- avoid recognition and attachment: capsules, M protein, Fc receptors
- survive within phagocyte: escape from phagosome, prevent phagosome-lysosome fusion, survive within phagosome
Capsules Confer Resistance to Phagocytosis
- Capsules hide the bacterial targets (PAMPs) of the phagocytic receptors (PRRs).
- The phagocytic response of the innate immune system is (temporarily) inhibited.
- APCs cells unable to present antigen to T-cells (via MHCII molecules).
- Bacteria continue to replicate.
- BUT… Immune system has evolved to develop a T-cell/thymus independent (TI) response to deal with encapsulated bacteria that avoid stimulating T-cell responses.
9
Q
Discuss the thymus dependent response
A
- Unencapsulated bacteria are susceptible to phagocytosis (provided they don’t use other evasion mechanisms).
- Proteinaceous bacterial antigens (TD antigens) can be presented to T-cells via MHCII molecules on APCs.
- Proteinacious bacterial antigens:
- Referred to as TD antigens because they require recognition by T-cells to elicit an immune response.
- Induce a long-lasting immune response due to formation of memory B-cells and T-cells.
- Production of anti-TD antigen antibodies is delayed, but antibodies are of high affinity and of multiple isotypes (IgA, IgM, IgG1, IgG2a, IgG2b, IgG3)
10
Q
Discuss the thymus independent response
A
- Encapsulated bacteria are able to (temporarily) evade phagocytosis.
- Proteinaceous bacterial antigens (TD antigens) can’t be presented to T-cells via MHCII molecules on APCs.
- BUT, bacterial capsules:
- Referred to as TI antigen because they don’t require recognition by T-cells to elicit an immune response.
- TI antigens do not give rise to immunological memory.
- TI antigens divided into TI type 1 (TI-1) and TI type 2 (TI-2) antigens based on their interaction with B-cells.
- Humans/animals with T-cell deficiencies are able to make antibodies against bacterial antigens through a TI response.
11
Q
Discuss TI-1 antigens and interactions with B cells
A
- e.g. LPS, bacterial DNA in high concentrations:
- Directly stimulate (i.e. inducing proliferation and differentiation of) both immature and mature B cells in the absence of T-cell help.
- Capable of directly stimulating B cells regardless of their antigen specificity (polyclonal activation*).
- Rapid antibody production in infants and adults (primarily IgM because TI-1 antigens do not induce isotype switching).
- *Polyclonal B-cell activation results in a non-specific antibody response because specific TI-1 antigen binding to surface Ig not necessary (B-cell-activating moiety of TI-1 antigen sufficient to induce proliferation and antibody secretion)
- Directly stimulate both immature and mature B cells in the absence of T-cell help.
- Rapid antibody production in infants and adults.
- Only B cells specific for the TI-1 antigen bind enough of it to focus its B-cell activating properties onto the B-cell*.
- *Only those B cells whose B-cell receptors also specifically bind the TI-1 molecules become activated. Gives a specific antibody response to epitopes on the TI-1 antigen.
12
Q
Discuss TI-2 antifens and interactions with B cells
A
- e.g. bacterial capsules, viral envelopes:
- High molecular mass repetitive polysaccharide structures.
- Activate only mature B-cells (immature B-cells are inactivated by repetitive epitopes).
- Since most of the B-cells in infants are immature, they do not make antibodies against TI-2 antigens efficiently.
- Contain no intrinsic B-cell-stimulating activity.
- Simultaneously cross-link B-cell receptors of mature B-cells specific for the TI-2 antigen, resulting in production of antigen-specific antibodies.
- Rapid antibody production in individuals over 5 years of age (primarily IgM, but also some IgG- isotype switching induced by co-stimulatory signals from TH cells).
13
Q
Which type of B cells respod to TI-2 antigens?
A
Only Certain Types of Mature B cells Can Respond to TI-2 Antigens**
- Spleen marginal zone (MZ) B cells:
- Unique set of nonrecirculating B cells in the spleen.
- Rare at birth and take years to mature in children, also underlying the lack of antibody response in infants to TI-2 antigens.
- B-1 cells/CD5 B cells:
- Autonomously replicating subpopulation of B cells.
- Reside mainly in the pleural and peritoneal cavities, but also found in the blood and spleen.
14
Q
Compare and contrast Ti and TD responses
A
TD antigen:
TI antigen:
15
Q
Compare and contrast TI-2 AND TD respones
A
TI-2 responses:
- rapid antibody production
- no memory
- restricted isotypes
(extrafollicular)
TD resposnses:
- Delayed production
- extensive class switching
- memory
- high affinity antibody
(GC reaction, leading to extrafollicular response)
