Lesson 65: Adaptive immune response to pathogen

Extracellular and intracellular pathogen

Some pathogen always remain in extracellular space

Some require intracellular space to reside and replicate

Some pathogens are facultative: either extracellular or intracellular

Some intracellular will temporarily be extracellular when leaving or entering

Extracellular

Virus, bacteria, protozoa, fungi, worm

Innate: Phagocytic cells, complement system

Adaptive: Antibody

Intracellular

Infect host cell: Virus, some bacteria, some protozoa

• Innate: NK cells

• Adaptive: CTL

Engulfed by phagocytic cells and some can replicate in them

• Adaptive: TH 1 cytokine activated macrophage

T helper lymphocyte

Express CD4 molecules that bind to MHC II molecules expressed on APC

• Ensures that Th-cells are activated by peptides from proteins engulfs from extracellular space

• From extracellular microbes mainly

• Th-cell cytokines will help B-cells make antibody that targets microbes when outside of cells.

Cytotoxic T lymphocyte

Express CD8 that bind to MHC 1 molecule by host cells with nuclei

How can antigen made inside cell end up in APC for presentation

Host cell can be killed by NK or CTL and antigen can end up in extracellular space

How can antigens outside cells get presented to CTL

APC can engulf antigen from extracellular space and present it via MHC I molecules to CTL

What targets extracellular pathogen

Phagocytic cells

Complement cascade

antibody

What target intracellular pathogen

NK cell

CTL

DTH response: Only adaptive and intracellular

Immune response to protozoa

Innate

• In general, innate responses to protozoa are similar to those for bacteria and viruses, reflecting whether the pathogen is in an extracellular or intracellular space.

Adaptive

• Protozoa stimulate both antibody and cell-mediated adaptive immune responses.

• Antibody (adaptive) and Complement (innate) can target extracellular stages, along with phagocytic cells (innate)

• Th-1 cytokine activated CTLs and macrophages can target intracellular stages. Along with NK cells (innate)

• Some protozoa have complex life cycles, and the immune responses may only be able to target some of the life cycle stages

Why are helminths good at avoiding immune mechanisms

Large size and complex nature

Helminths express PAMPs and release antigenic molecules. APCs present helminth antigens to T-helper cells.

Primarily a Th-2 cytokine response, generating mainly IgE antibody.

• Parasite-specific IgE binds mast cells. When parasite antigens bind the IgE Fab region, the mast cells degranulate.

• Mast cell granules result in inflammation: vasodilation, tissue edema, recruitment of Eosinophils.

• Often observe an eosinophilia

• Eosinophil release pro inflammatory causing helminths to detach. Inflammation leads to peristalsis and helps expel helminth

• IgE and IgG can coat helminth. Eosionophils for these receptors can release toxic substance. Macrophages can help wall them off

Immune response often contributes to helminth pathology

Innate immune response to fungal infection

Challenge for immune response due to large colony size and hard to control

Fungi breach inate barrier of respiratory tract

Phagocytic cells can phagocytize but not effective because hyphae to large

Innate response often leads to inflammation

APC can present antigen to T helper cell

The most helpful response is the antigen-specific activation of T-helper 1 cells and the production of IFN-y with enhancement of macrophage function. Often results in granulomatous (chronic) inflammation.

• Some antibody production will also occur and may facilitate phagocytosis and NK cell function

Bacterial evasion of immune response

Some bacterial pathogens can interfere with the signals downstream of innate immune activation that are required for the generation of an adaptive immune response.

Chlamydia, for example, secretes a protein called CPAF into the cytoplasm of cells – this is a protease that degrades transcription factors required for the expression of MHC class I and II (MHC-I and MHC-II) molecules.

H. pylori VacA inhibits the activation of helper T cells by blocking the loading of MHC class II molecules and by preventing T-cell receptor signaling.

Other bacterial secreted effectors (dotted lines) might interfere with the processing and loading of exogenous protein antigens onto MHC class I molecules during a process called cross-presentation, or take the function of the host proteasome to their own advantage

Viral immune evasion

• Sabotage of cytokine and chemokine cellular communication

• Disruption of NK cell mediated defense mechanism

• Subversion of MHC antigen processing and presentation

• Escape from humoral immunity by antigenic drift and shift

• Interference with complement cascade driven protection

• Short circuiting of apoptosis

Why are fungi so good at evading the immune system

Outer cell wall polysaccharide

Fungi evasion

• Cell wall organization masks inner component from immune system

• Special structures

  • Asteroid bodies

  • presence of capsule

  • titan cell

  • capsule enlargement

  • dimorfism

Mechanism of parasite immune evasion

• Hiding of parasite

  • Intracellular habitat

  • cyst wall

• Location in lumen of GI or respiratory system

• Movement/migration

• antigen modification

  • Antigen variation

  • disguise

  • mimicry

  • shedding

• Inhibition of immune factors

  • cleavage of antibody

  • inactivation of complement

  • inhibition of macrophage

• Innate Immunity

  • anti inflammatory mechanism

• T cell

  • Immunosuppression

  • blocking antibody

  • diversion of immunity

• B cell

  • Antigenic variation

  • masked antigen (sugars, Ex. glycoprotein)

  • shared host antigen (mimicry)