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Lecture 8 Flashcards

1
Q

What is HLA

A

Human Leukocyte Antigen

  • a set of proteins on surface of all cells
  • critical for generation of adaptive immune response by B and T cells
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2
Q

What is the HLA in humans?

A

MHC

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3
Q

What does MHC stand for?

A

Major Histocompatability Complex

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4
Q

Characteristics of MHC

A
  • Complex of ~200 genes on short arm of Chr 6
  • Class I and II
  • heterodimeric
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5
Q

HLA Class I molecules

A
  • HLA -A, -B, -C
  • On all NUCLEATED cells
  • Density varies from tissue to tissue
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6
Q

HLA Class II molecules

A
  • HLA-DR, -DP, -DQ
  • Only expressed on a RESTRICTED SET of cells:
    o Antigen presenting cells (DCs & Mac.)
    o B lymphocytes & Activated T lymphocytes
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7
Q

What is the normal role of HLA molecules?

A

= present pathogen derived peptides to the immune system
–> recognition of virus infected cells

o Virus (pathogen) derived peptides are presented in the binding groove of HLA class I molecules on the surface of infected cells

o TCR present on the surface of circulating CD8 T cells (specifically recognising HLA I complex)

o Following CD8+ T cell recognition of infected cell, CD8+ T cell effector mechanisms are triggered

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8
Q

Bare Lymphocyte Syndrome Type I & II

A

= Rare form of SCID (severe combined immunodeficiency)

  • IFNy incr. expression of MHC molecules
  • CITA co-activator play central role in MHC expression regulation
  • Pro-inflam. cytokines, TLRs can have additional effect
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9
Q

What are the characteristics of a pathogen specific T cell Response following allograft rejection? (adaptive Immunity) (5)

A
  1. Latent Period
  2. Memory -2nd set rejection
  3. Specificity
  4. Passive transfer by lymphocytes
  5. CD4 T-cell responses provide assistance for antibody production by B-cells
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10
Q

Characteristics of HLA Complex

A

= most POLYMORPHIC human gene system
- HLA loci display variation at population level

  • HLA-B most common gene
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11
Q

HLA nomenclature - HLA locus/gene

A

The initial letter e.g. HLA-A, HLA-B, HLA-DR, etc.

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12
Q

HLA nomenclature - HLA specificity/type

A

e.g. HLA-B27

HLA-A24

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13
Q

Serological recognition

A

The recognition of molecule by specific antisera (antibody)

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14
Q

Genetic Analysis

A

The recognition of molecule by DNA sequencing

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15
Q

Sereological v DNA identification

A

Sereological equivalent = HLA-B8

DNA equivalent = HLA-B*8:01

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16
Q

HLA nomenclature - subtype

A

HLa-A*24:02

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17
Q

HLA nomenclature - synonymous substitute

A

HLA-A*24:02:01

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18
Q

HLA nomenclature - substitution in non-coding region

A

HLA-A*24:02:01:02

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19
Q

HLA nomenclature - protein expression

A

HLA-A*24:02:01:02L

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20
Q

HLA locus

A

A specific HLA gene

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21
Q

Haplotype

A

the combination of alleles from two or more loci located on the same chromosome
–> DOES NOT imply linkage disequilibrium

22
Q

Genotype

A

The combination of two haplotypes, one from each parent, inherited by an individual

23
Q

Linkage Disequilibrium

A

Presence of two loci on the same chromosome which are inherited together more frequently than would be expected based on the gene frequencies

24
Q

What is the most frequent HLA molecule in Caucasian populations

A

HLA-A*02:01

25
Q

How can HLA be detrimental to an individual?

A
  • Drug hypersensitivity reactions
  • Autoimmunity
  • Immune escape (cancer)
  • Transplantation
26
Q

Coeliac Disease & HLA

A

Associated w HLA-restricted T cell response to modified gliadin peptides

  • 90-95% HLA-DQ2
  • 5-10% HLA-DQ8

–> Go from normal glutamines on a-Gliadine peptide T-cell epitope to negatively charged glutamic acid residues via tissue transglutaminase

27
Q

Evidence that allograft rejection = immunologically mediated (5)

A
  1. Latent Period
  2. Memory - 2nd set rejection
  3. Specificity
  4. Passive transfer by lymphocytes
  5. Production of antibodies
28
Q

What are the detection methods of sensitisation to HLA antigens (4)

A

o Crossmatching against donor cells
o ID of HLA antibodies in recipients
o Level of sensitisation
o Donor specific antibodies

29
Q

How do you identify suitable HSCT donors?

A
  • Registry typing
  • Patient & Family typing
  • Matched unrelated donor typing
  • Donor searches
30
Q

What is Autologous transplantation?

A

in the same individual (autograft)

31
Q

What is Isologous transplantation?

A

between genetically Identical individuals (isograft) identical twins, inbred animals

32
Q

What is Homologous types of transplantation?

A

between individuals of the same species (allograft)

33
Q

What is Heterologous transplantation?

A

between individuals different species (xenograft)

34
Q

What is allograft rejection?

A

The stimulus for alloreactive immune responses (i.e. rejection) is genetic differences between individuals, particularly HLA molecules

35
Q

Which HLA has more allelic polymorphism?

A

HLA-B (>3000)

  •   HLA-A (>2000 alleles)
  •   HLA-C (>1500)
  •   Beta2m (1)
  •   HLA-DRA (7)
  •   HLA-DRB1 (>1353)
  •   HLA-DRB3/4/5 (>75)
  •   HLA-DQA1+B1 (>400)
  •   HLA-DPA1+B1 (>200)
36
Q

Which HLA allele is most common in Caucasian populations?

A

HLA-A2 (A*0201)

37
Q

Which HLA allele do Australian Aboriginals have?

A

DRB1*0412

38
Q

TCR present on the surface of circulating CD8 T cells, specifically recognise the HLA _____ peptide complex

A

Class 1

CD8. … CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor (TCR). Like the TCR, CD8 binds to a major histocompatibility complex (MHC) molecule, but is specific for the class I MHC protein.

39
Q

Immune destruction features of kidney grafts in:

Hyperacute rejection

(Time; effector mechanism; cause)

A

Within minutes

Effector mechanism: Ab

Cause: preformed cytotoxic antibodies to donor antigens

40
Q

Immune destruction features of kidney grafts in:

Acute rejection

(Time; effector mechanism; cause)

A

7-21 days

effector mechanism: CMI (+Ab)

Cause: development of allogeneic reaction to donor antigens

41
Q

Immune destruction features of kidney grafts in:

Chronic rejection

(Time; effector mechanism; cause)

A

Later than 3 months

Effector mechanism: CMI (+Ab)

Cause: disturbance of host/graft tolerance

42
Q

ABO blood type compatibility

O group

A

Only O

43
Q

ABO blood type compatibility

B group

A

B or O

44
Q

ABO blood type compatibility

A group

A

A or O

45
Q

ABO blood type compatibility

AB group

A

A. B, AB, O

46
Q

What cellular features are most common with acute rejection

A
  •   Widespread interstitial oedema and dense focal infiltration of cortex by lymphoid cells many lymphoblasts, monocytes
  •   Importance of T cells - CD4, CD8. Cytotoxic production
  •   I/F few changes
47
Q

What humoral features of acute rejection are less common?

A
  •   Platelet aggregates in the capillaries, small venules and arterioles
  •   Fibrin and polymorphs (similar to hyperacute): fibrinoid necrosis of walls of small arteries and arterioles
  •   Obliteration of vessels with microthrombi . Glomerular damage and loss and hyalinosis. Tubular necrosis
  •   I/F findings IgG, IgM, C 3 and fibrinogen demonstrable in the walls of arterioles.
48
Q

What features would you see with chronic rejection of a renal allograft?

A

æ  Occurs months to years after allograft

æ  Gradual relentless change

æ  Narrowing of vascular arterial lumen
•  Due to endothelial cell proliferation
• Fibrosis of blood vessel wall

æ  Graft ischemia, interstitial fibrosis, tubular atrophy

æ  Mechanism unclear
•  Chronic endothelial damage and endothelial proliferation
•  Ongoing cellular and vascular rejection
•  Immune complex deposition
•  Recurrence of original disease

49
Q

Which HLA’s are the only ones considered in the Australian National Organ Matching Program (NOMS)

A

HLA-A, -B, DR

50
Q

HLA Mismatching Predicts More than Graft Survival and Rejection Episodes

A

Predicts increase in:

  •  Frequency and potency of rejection treatment
  •  Serum Creatinine at 1 yr
  •  Immunosuppressive drug dosage
  •  Hospitalization for infection in first year
  •  Incidence of Non Hodgkins lymphoma
  •  Sensitization of recipient

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