Lecture 12: Immunodeficiency

Question 1

Recall the line of defences of immunity.

Answer 1

Question 2

Recall the anatomical and chemical barriers of the body.

Answer 2

Question 3

Recall the features of innate and adaptive immunity.

Answer 3

Question 4

Recall the cells of the immune system.

Answer 4

Question 5

Recall the phagocytes.

Answer 5

Question 6

Recall the production of ROS by phagocytes, Recall the key enzymes.

Answer 6

• NADPH oxidase generates Superoxide O2• Forms reactive oxygen species (ROS) e.g. H2O2 & OCl-(hypochlorite)
• NADPH oxidase inactive in unstimulated phagocytes (not fully assembled)
• Phagocyte activation results in an NADPH oxidase assembly (p40, p47, and p67 join p22 & gp91 in phagolysosome)
• Superoxide dismutase (SOD) converts O2-to microbicidal hydrogen peroxide (H2O2)
• Myeloperoxidase (MPO) converts O2-to microbicidal hypochlorite (OCl-)
• ROS in itself is insufficient to kill target microbes
• Now thought ROS cause a K+ influx into phagolysosomes - pH↑ - optimal for antimicrobial peptides/enzymes to act

Question 7

Recall the complement system.

Answer 7

Question 8

Recall the outcomes of complement activation.

Question 9

Recall the overview of the complement system.

Answer 9

Question 10

Describe NK cells.

Answer 10

• Spontaneous capacity to kill tumour and virus-infected cells via ‘natural cytotoxicity’
  
  • Perforin (pores) and granzymes (cleave caspases > apoptosis)
  • unlike cytotoxic T lymphocytes (CTL), NK does not require prior host immunisation
• Secrete high levels of IFN-γand TNF (cell proliferation, angiogenesis)
• Considered the innate equivalent of CD8+ cytotoxic T lymphocytes (CTL)

Question 11

Recall the cytolytic pathways of NK cells.

Answer 11

• CTL clones express a somatically rearranged T cell receptor (TCR) that recognizes MHC class I (MHC-I)-peptide complexes
• NK cells express an array of non-rearranged, germline-encoded ACTIVATING and INHIBITORY receptors:
  
  • Activating receptors e.g.NKG2D bind to ligands on ‘stressed’ cells e.g. MICA
  • Inhibitory receptors e.g. Killer Ig-like receptors bind to MHC-I
• NK cells important for catching virus-infected or tumour cells that downregulate MHC-I to evade CTL
• CTL or NK cell activation results in the polarized release of perforin and granzymes into the target cell

Question 12

Describe antibodies.

Answer 12

Question 13

Recall antibody functions.

Answer 13

Question 14

Recall how extracellular bacteria is critical for the clearance of extracellular bacteria and viruses.

Answer 14

Question 15

Recall the removal of immune complexes.

Answer 15

Question 16

Recall the T cells.

Answer 16

• CD4+ T-Helper (TH) lymphocytes activated by antigens on antigen-presenting cells (APCs) -secrete cytokines which stimulate different mechanisms of immunity and inflammation
• CD8+ Cytotoxic T lymphocytes (CTL) recognise antigens on infected cells and kill these cells via cytotoxicity -perforin (pore)/granzymes (cleave caspases > apoptosis)
• Cell-mediated immunity’ – immune responses (phagocyte activation, Ag-specific CTL responses) that don’t involve antibodies (humoral immunity)

Question 17

Recall the immunodeficiency disorder.

Answer 17

Question 18

What is PID?

Answer 18

Question 19

Recall the types of PID.

Answer 19

Question 20

Describe the disease CGD.

Answer 20

Question 21

Recall CGD pathology (molecular and cellular features).

Answer 21

• Microorganisms produce catalase -destroys any residual H2O2 in CGD phagocytes (immune evasion!)
• Uncontrolled infections stimulate a chronic T cell-mediated immune responses
• Granuloma formation -the characteristic histologic appearance of activated macrophages
• IFN-γ therapy enhances transcription of NADPH oxidase complex components and superoxide production by CGD neutrophils
• Significant improvement after CGD neutrophil superoxide production restored to ~10% of normal levels

Question 22

Describe complement deficiency.

Answer 22

• Deficiency in one or more of the complement proteins
• Can be either inherited (primary) or acquired (secondary)
• Often result in weaker immune response to infection

Question 23

Recall how complement deficiency relate to autoimmunity

Answer 23

Question 24

What is acquired complement deficiency?

Answer 24

Question 25

Recall how defects in adaptive immunity are classified.

Answer 25

Question 26

Describe PAD.

Answer 26

Question 27

Recall how maternal antibody plays a role in delayed diagnosis of PAD.

Answer 27

Question 28

Describe Agammaglobulinemia.

Answer 28

Question 29

Describe SCID.

Answer 29

Question 30

Describe Familial LHL.

Answer 30

Question 31

Recall the pathological features of Familial LHL.

Answer 31

Question 32

Recall the mutation variants of familial HLH.

Answer 32

Question 33

Recall the molecular features of HLH-associated inflammation

Answer 33

Question 34

What is secondary immunodeficiency?

Answer 34

• Also know as acquired immunodeficiency i.e. ’during life’
• Noninherited
• Wide spectrum of presentation and severity
• Major predisposing causes of infection and death
• Relatively common e.g. compared to rare PIDs
• Manifestations
  
  • increased frequency of common infections
  • unusual complications of infection -opportunistic infections