Basic mechanisms of immune defense

Associate Professor Susanne Brix PedersenSystems Biology of Immune Regulation , CBS, DTU Systems Biology

Immunity?

Consists of the following activities:

– Defense against invading pathogens (viruses & bacteria)

– Removal of 'worn-out' cells (e.g. old RBCs) & tissue debris (e.g. from injury or disease)

– Identification & destruction of abnormal or mutant cells (primary defense against cancer)

– Rejection of 'foreign' cells (e.g. organ transplant)

– Inappropriate responses:

• Allergies - response to normally harmless substances

• Autoimmune diseases

A delicate equilibrium

Challenges

• Discrimination between self and non-self

– bacteria

– fungi

– vira

– parasites

– (transplants)

• Evolution

• Dealing with non-pathogenic factors

Lethality from pathogenic factors

- induce tissue damage & produce disease largely by releasing enzymes or toxins that physically injure or functionally disrupt affected cells & organs

- can only reproduce in host cells & cause cellular damage or death by:

– depleting essential cellular components

– causing cellular production of substances toxic to cells

– transforming normal cells into cancer cells

– inducing destruction of cells because infected cells is no longer recognized as 'normal-self' cell

Immune cell subsets

Characteristics of the two parts

T cells

B cells

Antibodies

Memory

MHC - HLA

Diversity

Somatic hypermutation

Polymorphism

Granulocytes

Monocytes

Macrophages

Dendritic cells

NK cells

NK T cells

Complement

Pattern recognition

Characteristics of the two parts

T cells

B cells APC

Antibodies

Memory

MHC - HLA

Diversity

Somatic hypermutation

Polymorphism

Granulocytes APC

Monocytes APC

Macrophages APC

Dendritic cells APC

NK cells

NK T cells

Complement

Pattern recognition

Innate and adaptive immune responses

Immune cell locations

Lymphoid organs and lymphatics

Immune cell subsets

Ideally, selected T cells contain TCRs with low affinity for self MHC in combination with “non-self” antigens, but usually auto-reactive T cells also exists in the periphery

Central T cell tolerance

Discrimination between “self” and “non-self”

Every immune response depends on regulation at the single-cell level

The phases of an adaptive immune response

Antigen-presenting cells

Immature DCs takes up antigen

Antigen processing pathways

Antigen presentation pathways

MHC class I and II

TH TC

Antigen presentation – the 3 activating signals

3. Signal

Cytokines ↔ Cytokine receptors

Activation Proliferation Help or Killing

1. 2.

MHC molecules

Length of peptides:MHC class I >10 aaMHC class II: 10–30 aa

T cells

Helps:B cells

CD8+ T cellsMacrophages

Kills:Infected cellsTumour cells

Recognizes MHC II on APC

Recognizes MHC I on all cells

Activation of CD4+ T cells

Clonal expansion

T cell receptor

Timing in T cell activation

Induction of immunity

Importance of CD4+ T cells:

CD4+ T cells are central in providing help for CD8+ T cell and B cell activation

Activation of CD8+ T cells

Killing of virus-infected cells

Apoptosis is induced due to the action of perforin (making pores), and the granule-containing granzyme B, a serine protease which activates a variety of caspases.

CTLs in virus clearance

Meeting places (T – APC)

Antibodies

B cells – plasma cells - antibodies

T cell help for B cell activation

B cells – memory cells

Antibody classes

Antibody-mediated bacteria killing

Preference for ”opsonized” bacteria

Different biological effects of antibodies

Activation of adaptive immunity

Christensen, HR (2003)

The ”patterns” of microorganisms

Pattern recognition in APC

Takeda & Akira, Int. Immunol. 2005

Recognition of ”pathogenic” structures

• Direct recognition of pathogens – ”danger signals” (viral, bacterial, fungal, parasitic)

• Innate immune system alerts the adaptive immune system in parallel with antigen-presentation

• Must recognize vital structures!

Cytokines are important polarizing agents

Zeuthen, LH (2006)

Antigen presentation

3. Signal

Cytokines ↔ Cytokine receptors

Activation Proliferation Help or Killing

1. 2.

Cytokines are important polarizing agents

Zeuthen, LH (2006)

Activation of CD4+ T cells requires formation of the immunological synapse

Activation or inhibition? Importance of co-stimulatory signals and cytokines

Regulation of the immune response

’Summing up’ questions

• What is the origin of the antigens presented on MHC I and MHC II?

• Which cell types display MHC I and MHC II, and to which type of T cells do they bind?

• How are a) bacteria, b) vira and c) cancer cells fought by the immune system?

• How is the human immune system dealing with the rapid evolution of microorganisms?

• What happens when an immune response is finishing and what happens if an immune response is not terminated upon elimination of the pathogen?