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INFECTION AND IMMUNOLOGY > ML Watson Lec 5 > Flashcards

ML Watson Lec 5 Flashcards

1
Q

In RA, activated tissue cells produce ______ (especially ______)

A

Chemotaxins

- Especially chemokines

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2
Q

Chemokine attract leukocytes such as n____, m____ and _ and _ _____

A

Neutrophils, monocytes and T and B lymphocytes

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3
Q

Tissue cells and invading leukocytes can be further activated after being attracted to the synovium leading to the product of…

1) Cytokines (TNFalpha and IL-1b)
2) Chemoattractants
3) P______
4) R______ O____ and N_____ S_____

A

Proteases

Reactive Oxygen and Nitrogen Species (RONS)

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4
Q

Cartilage is made by _____ in the matrix

A

Chondrocytes

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5
Q

Joint cartilage comprises mainly

1) F____ _____ (collagen)
2) P_______

A 
Fibrous Protein (collagen)
Proteoglycan
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6
Q

Bone is a dense connective tissue made up of cells and matrix it comprises:

1) Mineralised (C_____ P____) matrix
2) Fibrous protein C_____

A

Mineralised Calcium Phosphate Matrix

Fibrous protein - Collagen

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7
Q

______ break down bone when activated by cytokines (that may be released from T cells and macrophages)

A

Osteoclasts

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8
Q

Osteoclasts release

1) ____ _____
2) _ _ _s
3) ____ _____

A

1) Carbonic anhydrase - H+
2) Matrix metallo proteinases
3) Cysteine proteases

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9
Q

P____ is lost rapidly in RA

  • Shock absorption is impaired
  • Loss of joint function, pain
A

Proteoglycans

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10
Q

P______ breakdown proteoglycans (in cartilage)

A

Proteinases

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11
Q

Native collagen is only susceptible to degradation by ______

A

Collagenases

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12
Q

S_____ F_____ secrete the following when activated:

  • Lipid mediators (PGE2)
  • Cytokines (IL-6, IL-8, etc.)
  • Enzymes
  • Matrix materials

They act to ‘nurse’ T cells and may exhibit ‘malignant’ phenotype

A

Synovial Fibroblasts

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13
Q

Proteoglycan has a ‘shock absorber’ function

1) - It consists of chondroitin sulphate (polysaccharide) linked to ______ (core protein)
2) - It is charged (as it is highly S______ ) and binds water

What happens if it breakdown and cannot bind water?

A

1) Aggrecan
2) Sulphated

Friction in the joint will increase

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14
Q

MMPs are activated by removal of the propeptide.

This is done by S____ P_____

A

Serine Proteases

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15
Q

What is important on a matrix metalloproteinases’ domain structure for specificity and regulation?

A
  • The C terminus
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16
Q

What is the active site on a MMP?

A

Zn+

17
Q

What series of MMP inhibitors target the active site?

A
  • Hydroxamate series e.g marimastat
18
Q

What are MMPs inhibited by?

A
  • TIMPs - tissue inhibitors of Metallo-Proteinases
19
Q

Synthetic MMP inhibitors include Peptidomimetics. What acid are these based on?

A
  • Hydroxamic acid based molecules
  • Zinc binding
  • Mimic MMP substrate - collagen
  • Inhibit MMP activity
20
Q

Give an example of a Peptidomimetic that lacks specificity and acts on most metalloenzymes (similar structure to the substrate that acts on Zn binding region)

A
  • Marimastat
21
Q

Give an example of a Non-peptide hydroxamate that is involved in Zn binding by binding to the MMP active site.

A
  • Prinomastat

Better selectivity for collagenases

22
Q

Name the last type of MMP inhibitor after Peptidomimetics and Non-peptide hydroxcamates…

A
  • Tetracycline and derivatives e.g Doxycycline (periostat)

Used in periodontal and skin disease

23
Q

Name 3 roles the MMP’s have in the body involved with homeostatic connective tissue turnover…

A

1) Embryogenesis
2) Wound healing
3) Growth and repair

24
Q

Serine and Cysteine proteases are products of _____?

A
  • Leukocytes
25
Q

Give an example of 3 Serine and Cysteine proteases that break down matrix proteins such as elastin, laminin and Chondroitin sulphate and proteoglycans.

A

1) Neutrophil elastase
2) Cathepsin G
3) Kallikrein

26
Q

What are Serine and Cysteine proteinases inhibited by endogenously?

How are these inhibitors inactivated?

A

Serpins
(SERine Protease INhibitors)

  • Inhibited by oxidation
27
Q

What produces RONS?

A
  • Infiltrating leukocytes and tissue resident cells
28
Q
  • NADPH catalyses formation of ______ (O2-)
  • O2- dismuted to form _____ H2O2
  • H2O2 further decomposes to form
  • hydroxyl radical OH
  • hypohalous acids e.g HOCl-
  • These are powerful anti-bacterial agents
A
  • Superoxide

- Peroxide

29
Q

Leukocytes phagocytose:

  • Bacteria
  • Yeast
  • Immune complexes
  • DAMAGED TISSUE (produced in response to this)

What do leukocytes generate as part of their defence?

A
  • ROS
  • Reactive oxygen species
  • These are released into the joint space and cause further damage and inflammation
30
Q

Rheumatoid synovial tissue undergoes cycles of hypoxia and reperfusion leading to oxidative stress.

This can cause immune complex formation in some diseases leading to the generation of…

S______ (O2-), H2O2 and NO

A

Superoxide

31
Q

Superoxide (O2-), ____ and __ can:

  • Mediate important cell functions
  • Promote formation of hydroxy radical (OH), peroxynitrite (ONOO-)
  • Tissue injury, modulation of cell function
A

1) H2O2

2) NO

32
Q

RONS can lead to DNA damage and activation of inflammatory gene transcription (NFkB)

RONS can also cause amino acid modifications that can make host proteins immunogenic and inactivate serpins

What happens when serpins are inactivated?

A
  • Inactivation of serine protease inhibitors causes serine proteases to continue breaking down peptides in cartilage and bone
33
Q

Tissue damage in RA:

1) Inflammatory mediators and RONS from infiltrating leukocytes act on resident cells such as C_____, O_____ and F_____
2) These produce Proteases, MMPs, Elastases and _ _ _s and so do infiltrating leukocytes
3) These destroy cartilage and bone

A
  • Chondrocytes, osteoclasts and fibroblasts

- RONs (reactive oxygen and nitrogen species)

INFECTION AND IMMUNOLOGY (14 decks)

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